Adenomyosis scientific articles. Complex treatment of patients with adenomyosis. Recommended list of dissertations

Adamyan L.V.

Endometriosis remains an unresolved scientific and clinical problem, the main debatable issues of which include the following: is endometriosis always a disease; mechanisms of development and classification; genetic and immunological aspects of endometriosis; external, internal endometriosis and adenomyosis; retrocervical endometriosis; endometriosis and pelvic pain; endometriosis and adhesive process; endometriosis and infertility; diagnostic criteria; traditional and non-traditional approaches to diagnosis and treatment. Examination, treatment and monitoring of more than 1300 patients with endometriosis made it possible to determine the authors' own positions regarding the morphofunctional, endocrinological, immunological, biochemical, genetic aspects of endometriosis and to develop alternative treatment programs.

Concepts of etiopathogenesis

The definition of endometriosis as a process in which a benign growth of tissue occurs outside the uterine cavity, similar in morphological and functional properties to the endometrium, has remained unchanged over the past century. The following main theories of the occurrence of endometriosis remain a priority:

implantation theory based on the possibility of transferring the endometrium from the uterine cavity through the fallopian tubes into the abdominal cavity, described in 1921 by J.A. Sampson. There is also a possibility of endometrial translocation during surgical interventions on the uterus and dissemination of endometrial cells by the hematogenous or lymphogenous route. It is the hematogenous pathway of "metastasis" that leads to the development of rare forms of endometriosis with damage to the lungs, skin, muscles;

a metaplastic theory that explains the appearance of endometrial-like tissue by metaplasia of the mesothelium of the peritoneum and pleura, the endothelium of the lymphatic vessels, the epithelium of the tubules of the kidneys and a number of other tissues;

dysontogenetic theory, based on the possibility of disruption of embryogenesis and the development of endometrioid tissue from abnormally located rudiments of the Müllerian canal. According to the observations of the authors of the article, endometrioid lesions are often combined with congenital anomalies of the genital organs (bicornuate uterus, accessory uterine horn, which impede the normal outflow of menstrual blood).

The key moment in the development of endometriosis - the occurrence of endometrioid heterotopia - has not yet been explained by any of the theories. Undoubtedly, this requires that the endometrial cells have an increased ability to implant, and the body's defenses are insufficient to ensure the clearance of ectopic endometrial cells. The implementation of these conditions is possible under the influence of one or more factors: hormonal imbalance; unfavorable ecology; genetic predisposition; immune disorders; inflammation; mechanical injury; disorders in the systems of proteolysis, angiogenesis and iron metabolism.

Endometriosis as a genetically determined pathology is one of the newest concepts, which is based on the presence of familial forms of the disease, the frequent combination of endometriosis with malformations of the urogenital tract and other organs, as well as the features of the course of endometriosis (early onset, severe course, relapses, resistance to treatment) with hereditary forms of the disease. The authors of the article described cases of endometriosis in a mother and eight daughters (endometriosis of various localization), in a mother and two daughters (endometrioid ovarian cysts), endometriosis in twin sisters. Based on cytogenetic studies, the relationship of the HLA antigen (Human leucocyte antigen) with endometriosis, quantitative and structural changes in chromosomes in endometrial cells (increased heterozygosity of chromosome 17, aneuploidy) have been established, it has been suggested that bilateral endometrioid cysts can arise and develop independently from different clones. The detection of specific genetic markers in the future will make it possible to identify genetic predisposition, carry out prevention and diagnose preclinical stages of the disease.

The immunological aspects of endometriosis have been intensively studied since 1978. Of interest are data on the presence of changes in general and local immunity in patients with endometriosis, which play a certain role in the development and progression of the disease. Some researchers believe that endometrioid cells have such a powerful aggressive potential that they cause damage to the immune system.

The intravital phase-interference images of peritoneal fluid and peripheral blood cells obtained by the authors of the article in patients with deep infiltrative endometriosis convincingly indicate the active participation of the immune system in the pathogenesis of this disease. Most of the current studies are devoted to the role of peritoneal macrophages, cytokines, integrins, growth factors, angiogenesis and proteolysis, which favor the implantation of endometrial cells and cause pro-inflammatory changes in the peritoneal environment. production (in particular, dioxins), the occurrence of endometriosis.

Thus, the main etiopathogenetic factors of endometriosis should be considered retrograde menstruation, coelomic metaplasia, activation of embryonic residues, hematogenous and lymphogenous metastasis, genetic predisposition, iatrogenic dissemination, disorders of the proteolysis system. Risk factors for the development of endometriosis are hyperestrogenism, early menarche, heavy and prolonged menstruation, menstrual blood outflow disorders, unfavorable environment, obesity, smoking, and stress.

Terminology and classifications

Endometriosis is traditionally divided into genital and extragenital, and genital, in turn, into internal (endometriosis of the uterine body) and external (endometriosis of the cervix, vagina, perineum, retrocervical region, ovaries, fallopian tubes, peritoneum, recto-uterine cavity). "Internal endometriosis" in recent years is increasingly considered as a very special disease and is designated by the term "adenomyosis". A comparative analysis of the morphofunctional features of internal and external endometriosis allowed a number of researchers to suggest that retrocervical endometriosis is an "external" variant of adenomyosis (adenomyosis externa). There are more than 20 histological variants of external endometriosis, including: intraperitoneal or subperitoneal (vesicular - cystic or polypoid), as well as muscular fibrous, proliferative, cystic (endometrioid cysts).

Over the past 50 years, more than 10 classifications of endometriosis have been developed, none of which is recognized as universal. One of the most widely used in world practice was the classification proposed in 1979 by the American Fertility Society (since 1995 - the American Society for Reproductive Medicine) and revised in 1996, based on the calculation of the total area and depth of endometrioid heterotopias, expressed in points : stage I - minimal endometriosis (1–5 points), stage II - mild endometriosis (6–15 points), stage III - moderate endometriosis (16–40 points), stage IV - severe endometriosis (more than 40 points). The classification is not without drawbacks, the main of which is the frequent discrepancy between the stage of spread, determined by scoring, and the true severity of the disease. The authors of the article use their own clinical classifications of endometriosis of the uterine body, endometrioid ovarian cysts and retrocervical endometriosis, which provide for the allocation of four stages of the spread of endometrioid heterotopias. Undoubtedly, the true severity of the disease is determined by the clinical picture that characterizes the course of a particular variant of the disease.

Malignancy of endometriosis

For the first time, the malignant degeneration of endometriosis was reported by J.A. Sampson in 1925, having determined the pathological criteria for a malignant process in an endometrioid focus: the presence of cancerous and benign endometrioid tissue in the same organ; the occurrence of a tumor in the endometrioid tissue; complete encirclement of tumor cells by endometrioid cells.

The clinical course of malignant endometriosis is characterized by the rapid growth of the tumor, its large size, and a sharp increase in the levels of tumor markers. The prognosis of the course is unfavorable, the survival rate for non-disseminated forms is 65%, for disseminated forms - 10%. The most common variant of malignant tumors in endometrioid heterotopias is endometrioid carcinoma (about 70%). With widespread endometriosis, even after removal of the uterus and appendages, the risk of endometrioid tissue hyperplasia and malignancy of extraovarian endometriosis remains, which can be facilitated by the appointment of estrogen replacement therapy.

Extragenital endometriosis

Rare forms of endometriosis that require a special approach are extragenital foci that can exist as an independent disease or be components of a combined lesion. In 1989, Markham and Rock proposed a classification of extragenital endometriosis: class I - intestinal; class U - urinary; class L - bronchopulmonary; class O - endometriosis of other organs. Each group includes variants of the disease with or without a defect (with or without obliteration) of the affected organ, which is fundamentally important in determining treatment tactics.

Diagnostics

F. Konincks in 1994 suggested that the term "endometriosis" refer only to the anatomical substrate; and a disease associated with this substrate and manifesting certain symptoms is called "endometrioid disease." Adenomyosis is detected in histological preparations in 30% of women who have undergone a total hysterectomy. The incidence of external endometriosis is estimated to be 7–10% in the general population, reaching 50% in women with infertility and 80% in women with pelvic pain. Endometriosis most often occurs in women of reproductive age (25–40 years), often combined with uterine myoma, hyperplastic processes in the endometrium, obstructive malformations of the genital organs.

The final diagnosis of external endometriosis is possible only with direct visualization of lesions, confirmed by histological examination, which reveals at least two of the following signs: endometrial epithelium; endometrial glands; endometrial stroma; hemosiderin-containing macrophages. It should be remembered that in 25% of cases, endometrial glands and stroma are not found in the foci, and, on the contrary, in 25% of cases, morphological signs of endometriosis are found in samples of visually unchanged peritoneum. The final diagnosis of adenomyosis is also established by pathomorphological examination of the material when the following signs are detected: endometrial glands and stroma at a distance of more than 2.5 mm from the basal layer of the endometrium; reaction of myometrium in the form of hyperplasia and hypertrophy of muscle fibers; an increase in the glands and stroma surrounding the hyperplastic smooth muscle fibers of the uterus; presence of proliferative and absence of secretory changes.

The most important clinical symptoms of endometriosis, which determine indications for treatment, are pelvic pain, disruption of normal menstrual bleeding, infertility, and dysfunction of the pelvic organs. The severity and set of manifestations of the disease vary individually. A symptom characteristic of adenomyosis - menometrorrhagia and perimenstrual spotting of the "daub" type, is due to both cyclic transformations of the ectopic endometrium and a violation of the contractile function of the uterus. Pelvic pain, usually aggravated the day before and during menstruation, is typical of both external endometriosis and adenomyosis.

Complaints of dyspareunia are presented by 26-70% of patients suffering from endometriosis with a predominant lesion of the retrocervical region, sacro-uterine ligaments. This symptom is due to both obliteration of the retrouterine space with adhesions, immobilization of the lower intestines, and direct damage to the nerve fibers by endometriosis. A fairly common occurrence is the absence of pain in endometrioid cysts of considerable size. At the same time, intense pelvic pain often accompanies mild to moderate pelvic endometriosis and is presumably due to changes in prostaglandin secretion and other pro-inflammatory changes in the peritoneal environment. When assessing the severity of pain, they rely on the subjective assessment of the patient, which largely depends on her personal characteristics (psycho-emotional, socio-demographic).

Another symptom characteristic of endometriosis (in the absence of other apparent causes) is infertility, which accompanies this pathology in 46–50%. Causal relationships between these two conditions are not always clear. For certain variants of endometriosis, it has been proven that infertility is a direct consequence of such anatomical damage as adhesive deformity of the fimbriae, complete isolation of the ovaries by periovarian adhesions, damage to ovarian tissues by endometrioid cysts. The role of factors supposedly involved in the development of endometriosis or being its consequence is more controversial: violations of the ratio of hormone levels leading to inferior ovulation and / or functional inferiority of the corpus luteum, endometrium; disorders of local (increased levels of pro-inflammatory cytokines, increased suppressor/cytotoxic population of T-lymphocytes, growth factors, activity of the proteolysis system) and general (decrease in the number of T-helpers/inducers and activated T-lymphocytes, increased activity of natural killers, increased content of T-suppressors /cytotoxic cells) immunity.

One of the most important methods for diagnosing endometriosis, despite the widespread introduction of ultrasound and laparoscopy into practice, remains a bimanual gynecological examination, which makes it possible to detect, depending on the form of the disease, a tumor-like formation in the uterine appendages, an increase in the uterus and limitation of its mobility, compaction in the retrocervical region. , pain on palpation of the walls of the small pelvis and sacro-uterine ligaments. With endometriosis of the vaginal part of the cervix and vagina, on examination, endometrioid formations are visible.

Comparative studies of the effectiveness of various methods have made it possible to determine the diagnostic complex, which, with the greatest degree of accuracy, establishes the clinical and anatomical variant of endometriosis. Ultrasound is considered the optimal and generally available screening method in the algorithm for examining patients with various forms of endometriosis (endometrioid ovarian cysts, retrocervical endometriosis, adenomyosis), although it does not reveal surface implants. As the quality of diagnostics of adenomyosis using ultrasound, magnetic resonance imaging (MRI) and spiral computed tomography (SCT) improves, the use of hysterosalpingography becomes less relevant, especially since the diagnostic value of this method is limited. MRI and SCT have the greatest diagnostic value in endometrioid infiltrates of the retrocervical zone and parametrium, allowing to determine the nature of the pathological process, its localization, relationship with neighboring organs, and also to clarify the anatomical state of the entire pelvic cavity. For the diagnosis of endometriosis of the cervix, colposcopy and hysterocervicoscopy are valuable methods.

Currently, the most accurate method for diagnosing external endometriosis is laparoscopy. More than 20 types of superficial endometrioid lesions on the pelvic peritoneum have been described in the literature: red lesions, fire-like lesions, hemorrhagic vesicles, vascularized polypoid or papillary lesions, classic black lesions, white lesions, scar tissue with or without some pigmentation, atypical lesions, etc. The presence of Alain-Masters syndrome indirectly confirms the diagnosis of endometriosis (histologically - in 60-80% of cases).

Laparoscopic signs of a typical endometrioid cyst are: an ovarian cyst with a diameter of not more than 12 cm; adhesions with the lateral surface of the pelvis and / or with the posterior leaf of the broad ligament; thick chocolate content. The accuracy of diagnosing endometrioid cysts during laparoscopy reaches 98-100%. Retrocervical endometriosis is characterized by complete or partial obliteration of the retrouterine space with immobilization by adhesions and / or involvement in the infiltrative process of the walls of the rectum or sigmoid colon, infiltrate of the rectovaginal septum, distal ureters, isthmus, sacro-uterine ligaments, parametrium.

Adenomyosis, which diffusely affects the entire thickness of the uterine wall with the involvement of the serous membrane, causes a characteristic "marble" pattern and pallor of the serous cover, a uniform increase in the size of the uterus or, in focal and nodular forms, a sharp thickening of the anterior or posterior wall of the uterus, deformation of the wall with a node of adenomyosis, hyperplasia myometrium. The effectiveness of diagnosing internal endometriosis using hysteroscopy is controversial, since the visual criteria are extremely subjective, and the pathognomonic sign - the gaping of endometrioid passages with hemorrhagic discharge coming from them - is extremely rare.

Some authors suggest performing a biopsy of the myometrium during hysteroscopy, followed by a histological examination of the biopsy. The detection of various tumor markers in the blood is becoming increasingly important in the diagnosis of endometriosis and its differential diagnosis and a malignant tumor. The most accessible at present is the detection of oncoantigens CA 19-9, CEA and CA 125. The authors of the article have developed a method for their complex determination in order to monitor the course of endometriosis.

Alternative management of patients with endometriosis

Treatment of endometriosis has become the most widely discussed aspect of this problem in recent years. An indisputable position today is the impossibility of eliminating the anatomical substrate of endometriosis by any of the interventions, except for surgery, while other methods of treatment provide a reduction in the severity of symptoms of the disease and restoration of the functions of various parts of the reproductive system in a limited contingent of patients. However, surgical treatment is not always appropriate or acceptable to the patient.

As an alternative, a trial (without verification of the diagnosis) drug treatment of minimal and moderate endometriosis, or rather, the symptoms allegedly caused by this disease, can be considered. Such therapy can only be undertaken by a doctor with extensive experience in the treatment of endometriosis, provided that masses in the abdominal cavity are excluded, there are no other (non-gynecological) possible causes of symptoms, and only after a thorough examination of the patient. although it leads to a decrease in the size of the formation and the thickness of its capsule, it contradicts the principles of oncological alertness.

Despite the data of a number of authors on the rather high effectiveness of hormonal therapy in relation to the pain symptom, the advantages of its positive effect on fertility over the surgical destruction of lesions have not been proven (reported pregnancy rates are 30-60% and 37-70%, respectively), the prophylactic value in regarding the further progression of the disease is doubtful, and the cost of the course of treatment is comparable to that of laparoscopy. On the other hand, in the absence of unequivocal statistical data in favor of surgical or medical treatment of minimal-moderate endometriosis, the choice remains with the patient.

The authors of the article prefer surgical removal of lesions, the adequacy of which depends on the experience and erudition of the surgeon. In case of endometriosis accidentally detected during laparoscopy, it is necessary to remove the foci without injuring the reproductive organs. The visually determined boundaries of the endometrioid focus do not always correspond to the true degree of spread, which makes it necessary to critically evaluate the usefulness of the intervention performed. a single block with the uterus.

With endometrioid cysts, it is fundamentally important to completely remove the cyst capsule, both for reasons of oncological alertness and to prevent relapses, the frequency of which after the use of alternative methods (punctures, cyst drainage, capsule destruction by various influences) reaches 20%. With a nodular or focal-cystic form of adenomyosis, it is possible to perform reconstructive plastic surgery for young patients in the amount of resection of the myometrium affected by adenomyosis, with the obligatory restoration of the defect, warning the patient of a high risk of recurrence due to the lack of clear boundaries between the adenomyosis node and myometrium. Radical treatment of adenomyosis can only be considered total hysterectomy.

Permissible dynamic monitoring or non-aggressive symptomatic treatment of patients with adenomyosis, as well as deep infiltrative endometriosis after the diagnosis is clarified by biopsy and histological examination. Drug therapy can become a component of treatment, the main burden on which falls when the effectiveness of surgical treatment is insufficient or it is refused. A special role is given to non-steroidal anti-inflammatory drugs (prostaglandin synthetase inhibitors), as well as hormonal or antihormonal drugs, the therapeutic effect of which is based on the suppression of steroidogenesis in the ovaries, the creation of a hypoestrogenic state or anovulation.

These are hormonal contraceptives, progestogens (medroxyprogesterone), androgen derivatives (gestrinone), antigonadotropins (danazol), gonadotropin-releasing hormone (GnRH) agonists (triptorelin, buserelin); a new generation of GnRH antagonists and progestogens are currently being tested. The drug must be selected strictly individually, taking into account side effects, if possible, starting with the least aggressive. In particular, GnRH agonists should be prescribed with caution to patients with impaired functional state of the central nervous system and autonomic regulation, which can be aggravated while taking drugs of this group, danazol, although quite effective, in high daily doses (400-800 mg) it has an adverse effect on the gastrointestinal tract, and also has androgenizing and teratogenic potential.

The preoperative appointment of GnRH agonists is discussed, the supporters of which justify its expediency by reducing the size of endometriosis foci, vascularization, and the infiltrative component. From the point of view of the authors of the article, this is unjustified, since as a result of such an impact, radical removal of heterotopias due to masking of small foci, identification of the true boundaries of the lesion in infiltrative forms, and exfoliation of the sclerosed capsule of the endometrioid cyst are difficult. Therapy with GnRH agonists is indicated as the first step in the treatment of symptoms of endometriosis in non-reproductive organs in the absence of obliteration. In the presence of obliteration (partial or complete), the method of choice is an operation involving related specialists, followed by hormonal therapy.

Postoperative treatment with GnRH agonists is advisable for women of childbearing age in advanced endometriosis, in whom radical removal of endometriosis foci was not performed in the interests of maintaining reproductive potential or due to the risk of injuring vital organs, as well as in patients at high risk of recurrence or persistence of the disease. With widespread endometriosis, postoperative hormonal therapy should be combined with anti-inflammatory and spa treatment, which prolongs the remission of the pain syndrome and reduces the risk of reoperations. The principles of add-back therapy to reduce bone loss and hypoestrogenic effects in GnRH agonist therapy include: progestogens; progestogens + bisphosphonates; progestogens in low doses + estrogens.

A special place among the options for hormonal treatment is hormone replacement therapy after radical surgery performed for endometriosis (hysterectomy with or without adnexectomy). The persistence of endometriosis foci with recurrence of symptoms after radical surgical treatment is described. Taking into account the risk of both possible recurrence and malignancy of residual lesions, estrogens are recommended to be used in combination with progestogens.

Recurrence or persistence of endometriosis after treatment is one of the most discussed problems in modern gynecology, due to the unpredictability of the course of the disease. Most authors agree that in the absence of a method that provides an accurate assessment of the adequacy of the performed intervention, the removal of the entire endometrioid substrate cannot be guaranteed by any surgical technique, and even more so by drug therapy. On the other hand, recognizing the role of systemic disorders in the pathogenesis of endometriosis, one cannot deny the possibility of de novo endometriosis.

The frequency of recurrence of endometriosis varies, according to different authors, from 2% to 47%. The highest frequency of recurrence (19–45%) of retrocervical endometriosis is associated both with the difficulty of determining the true boundaries of the lesion in infiltrative forms of endometriosis, and with a conscious rejection of an aggressive approach to removing foci located near vital organs.

Thus, endometriosis is characterized by paradoxical aspects of etiopathogenesis and clinical contrasts of the course, which have not yet been explained. Indeed, with a benign nature of the disease, an aggressive course with local invasion, wide distribution and dissemination of foci is possible; minimal endometriosis is often accompanied by severe pelvic pain, and large endometrioid cysts are asymptomatic; cyclic exposure to hormones causes the development of endometriosis, while their continuous use suppresses the disease. These mysteries stimulate further deepening and expansion of both basic and clinical research in all areas of the problem of endometriosis.

INTRODUCTION

CHAPTER 1 LITERATURE REVIEW

1.1 Epidemiology of endometriosis

1.2 Theories for 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 steroid receptor genes ERa and NR/I, PgR, AR

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 object of study

2.3 Methods and scope of clinical, instrumental and laboratory studies

2.3.1 Methods of clinical examination

2.3.2 Instrumental research methods

2.3.3 Laboratory research methods

2.3.4 Statistical processing of data

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

3.1 Frequency of adenomyosis in gynecological patients

3.2 Clinical and anamnestic features of patients with adenomyosis

CHAPTER 4 MOLECULAR GENETIC CHARACTERISTICS OF PATIENTS WITH ADENOMYOSIS

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

4.2 Expression of steroid receptor genes NRa, ER.fi, PgR, AR and CYP 19 (aromatase) in endometriosis

CHAPTER 5 RISK FACTORS AND A COMPREHENSIVE PREDICTION SYSTEM FOR ADENOMYOSIS

5.1 Risk factors for adenomyosis

5.2 Adenomyosis prediction computer program

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

BIBLIOGRAPHY

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Please note that the scientific texts presented above are posted for review and obtained through original dissertation text recognition (OCR). In this connection, they may contain errors related to the imperfection of recognition algorithms. There are no such errors in the PDF files of dissertations and abstracts that we deliver.

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 reproductive and menstrual dysfunctions, persistent pain syndrome, dysfunction of adjacent organs, as well as a deterioration in the general condition of patients, a decrease in their ability to work. The most common localization of genital endometriosis is the defeat of the uterus - adenomyosis, whose share in the structure of this pathology is 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 the correction of the results of morpho-biochemical studies.

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

To clarify the diagnosis, an instrumental examination was carried out: transabdominal and transvaginal ultrasound scanning using Aloka-630 (Japan), Megas (Italy) devices and hysteroscopy using Karl Storz endoscopic equipment (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 uterine cavity mucosa, followed by their histological examination, a control hysteroscopy was performed.

Histological material was processed according to the generally accepted method. Histochemical methods revealed the main substance of the connective tissue of the myometrium using alcian blue according to the method of A. Krieger-Stoyalovsky; the determination of neutral polysaccharides was carried out using the PAS reaction, the DNA of cell nuclei - according to the Felgen method, the macromolecular stability of tissue structures of the connective tissue - according to the method of K. Velikan.

The isolation of phosphoinositides (PIN) was carried out using an improved method of flow thin layer chromatography, which made it possible to determine the content of various PIN. 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 (mean age 39.3 ± 2.45 years).

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

The most characteristic complaints of patients were established: dysmenorrhea, which was noted by 34 (86.1%) women, menorrhagia - 17 (42.5%), pre- and postmenstrual blood discharge 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 in 13 (32.5%) patients. Every fifth woman had dysmenorrhea 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, 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 rest of the women, the uterus was enlarged up to 8-9 weeks of pregnancy. Pathological formations in the area of ​​the uterine appendages were not found in any patient, both in two-handed and in echographic studies.

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 the detection of adenomyosis was 77.5 ± 6.69%, hysteroscopy - 87.5 ± 5.29%.

A morpho-biochemical study was performed in 50 operated patients (mean age 42.6 ± 3.35 years) with adenomyosis verified by morphological examination. It was established that the growth of heterotopic foci was accompanied by a pronounced plethora 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 II-III degrees of damage. An uneven compaction and liquefaction of the argyrophilic substance with loss of the fibrous structure around the glands located in the myometrium was found. Violations of the structure of the ground substance and fibrous structures of the connective tissue skeleton 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 the result of emerging tissue hypoxia. The plethora of the microvasculature of the myometrium present in the samples and the accompanying edema of the perivasal spaces and pronounced lymphostasis can be considered a morphological manifestation of the latter. The pathological process, deeply infiltrating tissues, leads to ischemia of the nerves and their demyelination. The result of these processes is a change in the afferent input at the level of the segment of the spinal cord, the impulse entering the central nervous system changes steadily, which leads to a change in the sensory quality of pain and the appearance of the most painful sensations. Reflex vasospasm, which develops in response to a painful stimulus, exacerbates ischemic disorders, further enhances afferent impulses to the brain, contributing to the formation of "vicious circles" in sympathetic reflexes. In addition, the 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 violation of intracommunicative relationships in the blood-uterine tissue system. All this leads to the formation of a vicious circle, characterized by interrelated hormonal, immune, cellular disorders, which are extremely difficult to completely eliminate with hormonal drugs alone. This is evidenced by the low efficiency 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 can influence the regulation of cell proliferation and/or differentiation, especially in the endometrium. The occurrence of pain in patients with adenomyosis may be due to hyperproduction 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 via the so-called cyclooxygenase pathway. The main source of overproduction of prostaglandins are activated mononuclear cells. We conducted a study of the content of FIN in phagocytic mononuclear cells in patients with adenomyosis, assessing their content by their presence in monocytes. The content of FIN in the blood reflects the specifics 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 in patients with adenomyosis, the amount of the main FIN - phosphatidylinositol (PI) was significantly reduced by 1.3 times compared with the values ​​in women of the control group. The data obtained indicate that in patients with adenomyosis, FI deficiency plays a very important role in the processes of proliferation, which means that 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.). At the same time, the high cost of drugs does not allow them to be widely used in clinical practice. In this regard, patients with limited financial resources are prescribed progestogens, in which norethisterone acetate appears as an active substance - norkolut (Gedeon Richter, Hungary), primolut-nor (Schering, Germany).

The study of the results of traditional hormonal therapy and the method developed by us for the treatment of adenomyosis was carried out. The 1st group of patients included 20 women (mean age 38.2 ± 2.88 years) who received only hormonal therapy (norcolut - 10 mg per day from the 5th to the 25th day of the menstrual cycle for 6 months ). In the 2nd group of patients, which included 20 patients (mean age 39.4 ± 2.97 years), complex treatment was carried out using the following drugs: norkolut (dosing 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 developed by us (2004). A second course of laser therapy was performed after 2 months. The therapeutic efficacy of laser therapy is due to both the laser, infrared and magnetic effects of this device, as well as the specifics of the combined use of these types of energy. Hofitol is a herbal preparation with a pronounced hepato-, nephroprotective and diuretic effect, 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 hofitol 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 performed immediately after the end of menstruation, so that the course of treatment was not interrupted and kept 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 the 2nd group. Thus, improvement in general condition, well-being, mood was noted by 5 (25.0%) patients from the 1st group and 17 (85.0%) women from the 2nd group. Such changes had a favorable psycho-emotional effect and contributed to an increase in the working capacity of patients. Sleep improved in 2 (10.0%) women from the 1st group and in 10 (50.0%) women from the 2nd group; 1 patient from the 1st group and 8 women from the 2nd group 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 the 2nd group - in comparison with women who received traditional hormonal treatment. Thus, dysmenorrhea decreased in 11 (64.7%) patients from the 1st group and in 16 (94.1%) women from the 2nd group, and it was possible to stop it completely in 2 and 11 patients of the respective groups. Pain in the lower abdomen decreased in 4 out of 8 patients in the 1st group and in 9 out of 10 women in the 2nd group. It should be noted that patients from the 2nd group noted a decrease in the severity of the pain symptom and dysmenorrhea already in the next menstruation after laser therapy, which was carried out against the background of drug therapy. Dyspareunia decreased in 2 patients from the 1st group and in 6 women from the 2nd group. A decrease in the duration and intensity of menstrual blood loss was noted by 7 women from the 1st group and 10 women from the 2nd group. The lack of effect from the therapy, which led to surgery, was noted in 4 (20.0%) women from the 1st group and in 1 (5.0%) patient from the 2nd group, who were diagnosed with a diffuse-nodular form of adenomyosis .

Thus, the complex correction of disorders that occur in patients with adenomyosis contributes to an increase in the effectiveness of the treatment of this pathology. The inclusion of a non-steroidal anti-inflammatory drug (nurofen plus) in the complex therapy in patients with adenomyosis in patients with adenomyosis, as well as drugs that improve microcirculation, improves the effectiveness of treatment and reduces the frequency of surgical interventions by 4 times compared with patients who received traditional hormonal therapy.

Literature

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

Please help, my husband really needs a boy. I have an older daughter from a previous marriage, then we had a joint daughter. Now the husband directly demands the boy. Ready even for IVF with the planting of an embryo of the desired gender. But my gynecology told me that IVF is definitely not for me, hormonal preparation will have a very bad effect on my blood vessels and pressure. Up to a stroke. She also talked to her husband about it. He is going to take me to the border due to the fact that in our clinics (we were in two) they said they can do a transplant on the floor only for health reasons, and IVF may not be able to endure my health at all. Sister says that you need to try folk methods. And I'm scared. If the first ultrasound does not show the sex, then I don’t know what will happen on the second if it’s a girl again. Suddenly, the husband will be so against the girl that ... Or will he send for the fourth? Help! There are some ways to count the days, I once read about the right day of conception! for the desired floor. If anyone used this method and if you succeeded, please tell me, I beg you!

Lubakha

Hello girls.
In general, I began to think about an au pair (I have recently been alone with three children). In principle, I manage to do everything, but it costs me nerves and great physical effort ... I constantly look like a driven horse .... I can forget about putting on makeup and styling my hair in the morning, I don’t have time .... and so the whole day .. .tyk dyg, tyk so. In order to make life a little easier, I think at least once a week, to find an assistant, to do some cleaning. My first problem in my head ... is that I am really ashamed to seek help around the house, since I am physically healthy and, in principle, I can do everything myself (now I do it too). My second problem is in my head .... will I be satisfied with the cleaning? After all, a stranger is unlikely to clean up as well as at home. I'm not straight clean, but I never have a mess at home .... there are no scattered toys, clothes or dust tumbleweeds)). I resisted washing the floor with a mop for a long time, because I thought (and I still think) that it was just smearing dirt from corner to corner .. but physically I just can’t wash 100 square meters with my hands .... and the children won’t give me so much time for cleaning. On the one hand, I think that it would be great to take the children and go for a walk while the house is being put in order. And on the other hand, you suddenly have to wash everything over again .... and the money is not small.
In general, these are all my cockroaches, I agree. Who has au pairs and similar cockroaches ... how did you choose, according to what criteria, a cleaning lady? How often did you have to change, if necessary?

Nata Ser

What I don't understand is how can this be? About a year ago we moved into a new apartment, finally a big one. The renovation was done before us, I can’t say that everything is perfect, but overall it’s okay. And somewhere around August, the neighbors above us began repairs: the buzzing and drilling was terrible, the roar was noisy, but everything was strictly during working hours. Now, as I understand it, finishing work is going on there, because although there is noise, it’s different: tapping etc. But this is not the problem, a month ago, just like that on Sunday, a neighbor from below came to us and said that he had a leak in his bathroom from the ceiling. At that time, no one washed in our bathroom, but before that they used it, well, maybe half an hour ago ... We let him in, he made sure that everything was dry under the bathroom and in the toilet too. But today the doorbell rang again, flowing again. Yes, I was just in the bathroom and today everyone was there in turn. But, I took a bath yesterday, and before that on different days, nothing flowed either. And again it’s dry everywhere. She didn’t let her neighbor in, because she was in a negligee and talked to him through the door. He is indignant, demands that we call a plumber. But we need it, everything is dry with us. Could this be due to the renovation being done by the upstairs neighbors? And who still should call the plumber? It's not hard for me, but I don't understand why?

Sirens

Good Sunday morning!

This Thursday (which was), I was at a psychologist's consultation in kindergarten. At first I wanted to ask questions, but then I realized that, in principle, I still have a chamomile child, with my own quirks, Wishlist and pampering, of course, and tantrums (nowhere without it). After this consultation, they (the mothers who were) approached the teacher and asked how they (the children) behave in the group. And the teacher said about mine: “Of course she’s a hooligan, where would she be without it. She’s stubborn. But she’s like that girl in the video, if they beat her, then she’ll rather lie down and lie down, loves to pity the children, those who cry.” Basically, I was happy for my daughter. But, there is a small “but”, is it right, they will beat her, and she will lie. Of course, I would not want her to beat herself and take part in fights, but I also do not want her to lie down and be beaten. Can this be fixed somehow or is it not worth it, maybe I'm worried in vain? So that let them not give up, but fight back. Now I'm worried, but life is long. Of course, in the future I plan to give it to some kind of circle so that I know the tricks (for every fireman).

As a manuscript

SOROKINA ANNA VLADIMIROVNA

PATHOGENESIS, PREDICTION AND POST-GENOMIC DIAGNOSTICS OF ADENOMYOSIS

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

Moscow 2011

The work was performed at the Department of Obstetrics and Gynecology with the course of perinatology of the Federal State Budgetary Educational Institution of Higher Professional Education "Peoples' Friendship University of Russia".

Scientific consultants:

Honored Worker of Science 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 of the State Educational Institution of Higher Professional Education First Moscow State Medical University. THEM. Sechenov of the Ministry of Health and Social Development, MD K.G. Serebrennikova Professor of the Department of Obstetrics and Gynecology, Faculty of Pediatrics, Russian National Research Medical University. N.I. Pirogova, MD L.M. Kapushev Department of Pathological Physiology, Faculty of Dentistry, Moscow State University of Medicine and Dentistry, MD, Professor A.G. Rusanova

Lead organization:

SME MO "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, d.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 century-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 contingent of patients.

However, it is difficult to judge the prevalence of this disease with any accuracy, 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 occurrence and growth of endometrioid heterotopias.

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

In recent years, genital internal endometriosis of the body of the uterus (adenomyosis) is usually considered as a special disease that 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%. On the basis of 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 method of ultrasound diagnostics (ultrasound) has been widely used to diagnose adenomyosis, however, data on its information content are contradictory, since the visual characteristics of endometrioid 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, moreover, does not give a reliable diagnosis in 100% of cases (Bradley, 2009). Widespread in the West, office hysteroscopy has not yet won great popularity in our country due to the high cost of 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 the leading positions (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 ratio of mass to charge 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 performance and sensitivity (Baumann S., 2005; De Noo M.E., 2005; Alexandrov T. et al., 2010).

The literature describes examples of the successful application of this method to identify differences between the blood serum of patients with cancer of the stomach, rectum, prostate, endometrium, ovaries, 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) to conclude that the natural course of the disease at the initial stage is completely unpredictable. Particularly noteworthy are the data of the authors that the progressive course of adenomyosis is found in 2/3 of patients within a year from the date of diagnosis. At the same time, it is impossible to predict in which particular patients the pathological process will progress.

According to recent data, the effectiveness of the treatment of adenomyosis is determined by the degree of its activity, the establishment of which, especially at the preoperative stage, presents great difficulties (Unanyan 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) immunity system has changed. It was found that this system is activated not only in response to the introduction of infectious pathogens, but also in 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 reflect the degree of activation of innate immunity, as well as the state of the antiproteolytic (compensatory) potential.

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

Thus, a comprehensive determination of the above immunity indicators 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.

Summing up, it should be noted that, despite the large number of studies on 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 the expansion of knowledge about the molecular biological aspects of its pathogenesis.

Objectives of the study 1. To assess the information content of existing traditional methods for diagnosing adenomyosis.

2. To identify potential peptide markers of adenomyosis in blood serum and substantiate the possibility of their use for the diagnosis of this disease.

3. To compare potential peptide markers in the blood serum of 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 blood serum and the degree of activity of the course of adenomyosis.

5. Analyze the activity of Tx1 and Tx2 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 blood serum and the degree of activity of the course of adenomyosis.

7. Assess the possibility of using cytokines, growth factors, indicators of the nonspecific immunity system in the prediction and diagnosis of adenomyosis, as well as determining the activity of its course.

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

Scientific novelty The ideas about the pathogenesis of adenomyosis and its features are expanded, as well as clinical signs are shown with different activity of the course of the disease.

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

For the first time, proteomic profiling of blood serum using MALDI mass spectrometry determined diagnostic markers of adenomyosis, proved the possibility of differential diagnosis between adenomyosis and other gynecological diseases (uterine fibroids, endometrial hyperplasia, etc.) 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 synthesizing IF, TNF, and IL-2 are not directly involved in the development of adenomyosis, while Th2 cells synthesizing IL-6 and IL-10 play a significant role in immune responses 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, the relationship between the level of these indicators in the blood serum and the degree of activity of the course of adenomyosis was revealed, which is important in predicting the disease, as well as choosing the tactics of managing patients.

Based on a comprehensive study of innate immunity parameters in the 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 violations of the proteolysis system in predicting the disease was determined.

Practical significance An algorithm for examination, prognosis, early diagnosis and tactics of managing 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 tactics for managing 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 degree of spread of the process, disease prognosis, has been established. , choose the right method of treatment.

The use of the proposed diagnostic algorithm is advisable not only from a clinical point of view, but also from an economic one, 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 areas.

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

2. Changes in blood serum that occur in adenomyosis, determined using 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 the dissertation material The materials and main provisions of the dissertation were reported and discussed at the International Congresses: VI Regional Scientific Forum "Mother and Child" (Yekaterinburg, 2010), XI All-Russian Scientific Forum "Mother and Child" (Moscow, 2010), V Congress of the International Association of Reproductive 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).

Discussion of the dissertation took place at a joint scientific conference of employees of the Department of Obstetrics and Gynecology with the course of Perinatology of the Medical Faculty of the Federal State Budgetary Educational Institution of Higher Professional Education "Peoples' Friendship University of Russia" and practitioners 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 practical classes for advanced training of obstetrician-gynecologists of the FPC MR FSBEI HPE RUDN University.

The 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 literature index. 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 pathomorphological examination of the uterine body for genital prolapse.

To increase the specificity of the study, patients with adenomyosis in combination with uterine myoma 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 the materials of the gynecological departments of City Clinical Hospital No. 64, City Clinical Hospital No. 29, City Clinical Hospital No. 12, National Medical Center named after N.N. N.I. Pirogov of Roszdrav, outpatient department of the Federal State Institution Research Institute of Physical Chemistry of the Federal Medical and Biological Agency of Russia, N.N. N.N.

Blokhin RAMS of Russia.

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

36 (30%) out of 120 patients with adenomyosis underwent radical surgical treatment - removal of the uterus. In this group of patients, repeated sampling of blood serum was performed 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 myoma (n=60), endometrial hyperplastic processes (n=50), uterine body cancer (n=50) and ovarian cancer (n=60) stored in the laboratory of proteomics of the Institute of Bioorganic Chemistry.

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 the 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 the 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, pain syndrome and hyperpolymenorrhea, were assessed.

The degree of pain syndrome was assessed using the proposed MacLaverty C.M., Shaw P.W. (1995) systems 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. According to the severity, mild (Hb 90-110g/l), moderate (Hb 70-90g/l) and severe (Hb - below 70g/l) anemia were distinguished.

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

In accordance with the goal and objectives set, a program for examining patients was developed, which provides for a comprehensive study of the state of health, including traditional and special innovative examination methods (Fig. 1).

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

Close attention was paid to diseases transferred 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 DIAGNOSIS DIAGNOSIS Proteomic profiling of blood serum from Complaints, anamnesis data, using MALDI mass gynecological examination of spectrometry Determination of cytokines and growth factors in serum Ultrasound of the pelvic organs using enzyme immunoassay Determination of innate immunity 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 marriage is in a row. Reproductive function was assessed by the number of pregnancies, course, maternal and fetal outcomes. Attention was paid to the analysis of the number and characteristics of the course of childbirth, the frequency of their complications, and the use of surgical interventions.

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

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

Gynecological status was determined on the basis of examination of the external genital organs, examination of the vagina and cervix using mirrors, bimanual vaginal examination, and, according to indications, rectovaginal examination.

Of the laboratory methods, the studies were used as routine (clinical blood test, general urinalysis, determination of group and Rh blood affiliation, analysis of biochemical parameters and hemostasiograms, reflecting the function of the liver and kidneys, blood glucose, Wasserman reaction, test for HIV infection and HBS- antigen, electrocardiography, radiography of the chest cavity, bacterioscopic examination of the vaginal discharge), as well as modern highly informative imaging methods - ultrasonic transabdominal and transvaginal scanning of the pelvic organs on the Echoview 80 L Di and Aloka SSD devices - 636 and 650, hysteroscopy using rigid hysteroscopes of the type Hamou I (30°) and Hopkins II (30°) (Karl Storz GmbH & C0., Germany) with an outer diameter of 5 mm.

This work required blood serum obtained according to the 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 Laboratory of Proteomics of the Institute of Bioorganic Chemistry named after V.I.

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

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

Fractionation of blood sera was performed on 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, the resulting arrays of mass spectra were used to determine the combination of peaks that best distinguished the spectra of pathological samples from the control.

Mass spectrometric data were analyzed using the Genetic Algorithm (GA) and the Controlled Neural Network (SNN), 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 on the basis of the Department of Clinical and Experimental Immunology of the City Clinical Hospital No. 29 named after.

N.E. Bauman, Moscow (supervisor - Corresponding Member of the Russian Academy of Medical Sciences, Prof. S.G. Morozov).

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

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, which is in the blood serum in a complex with 1-PI, a spectrophotometric method was used using a set of reagents for the quantitative determination of the activity of leukocyte elastase in blood serum (ELASTASE) (Biofarm-test LLC, Moscow) and a set of reagents for the quantitative determination of the activity of 1-proteinase inhibitor in human blood serum (ALPHA-1-PI) (LLC "Biopharm-test", Moscow) in accordance with the Instructions for the 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 of the Russian National Research Medical University.

N.I. Pirogova of the Ministry of Health and Social Development of Russia, senior researcher Olimpiyeva S.P. using the program developed at the department for a personal computer, which allows comparing user-organized data groups using Student's criterion (T-criterion) and a statistical non-parametric criterion - Fisher's exact method, independent of the nature of the distribution of the indicator.

After comparing the groups for each feature, the information content of the complete feature space is evaluated separately to distinguish between all user-defined groups. To obtain such an estimate, a sliding test is carried out for the correctness of automatically assigning each individual to one of the compared groups using a sequential Baisen recognition procedure.

To generate graphs, as well as to check the normal distribution of quantitative traits, obtain descriptive statistics and compare the formed groups of patients using Student's criteria (T-test) and Mann-Whitney (for traits that have a non-normal distribution), the EXCEL 2003 and STATISTICS 6.0.

Research results and their discussion In this study, based on the analysis of the results of examination and treatment of 120 patients with adenomyosis and 50 patients without adenomyosis, data on the pathogenesis, 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 of 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 the course of adenomyosis), which does not differ significantly from the population data (12.2±1.54 years). Not all researchers agree with this point of view, considering the late onset of menarche as 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 small pelvis to retrograde menstrual blood is a factor risk of endometriosis of any localization.

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

Hypermenorrhea was observed with almost equal frequency in both groups (26.3% and 22.7%). These data indicate the inferiority of the mechanisms of regulation of 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 are of priority importance in the development of adenomyosis (Adamyan L.V., Kulakov V.I., 2006; Di W. et al., 2007; Zhao Z.Z. et al., 2008). Noteworthy is the high degree of burdened reproductive history in patients with adenomyosis, especially in the group with "active" adenomyosis (p

In the patients examined by us, there is a high frequency of chronic salpingo-oophoritis and endometritis in history - 51.6%; in the population, the average frequency of these diseases is 37.2%.

The findings support the notion that intrauterine interventions are risk factors for adenomyosis. A number of authors believe that favorable conditions for invasion and growth of endometrial cells in the myometrium create neurodystrophic changes in the zone of the histobiological barrier 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; Talbi S. et al., 2006;

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

The frequency 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 in "active" adenomyosis (p

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

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

When studying the history data, it was found that patients with adenomyosis had 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 and anamnestic data, patients with adenomyosis have a significant incidence of chronic diseases. So, 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 history in 9.2% of patients.

Allergic reactions to drugs and various household factors were observed in 22.5% of patients, which may indirectly indicate disorders of immune homeostasis.

Some patients had several of the above diseases. Depending on the degree of activity of the course 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 own results of the clinical course of adenomyosis in patients did not confirm significant differences in age, time of onset of menarche, number of births and heredity, depending on the degree of activity of the course 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 history, which was manifested by a lower health index in patients with "active" adenomyosis.

Thus, inflammatory processes of the genital organs and surgical interventions on the uterus are of great importance in the pathogenesis of adenomyosis. This is confirmed by studies proving that pregnancy often has an inhibitory effect on endometriotic lesions, and abortion 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 for 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 myoma, 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, a 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 for 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 hyper- and underdiagnosis of adenomyosis, which determine the erroneous tactics of management 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. So, out of 120 patients, this diagnosis was made correctly in 49%, in 18% adenomyosis was mistaken for uterine myoma, 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 neuropathologist, gastroenterologist, therapist with suspicion of disc herniation, osteochondrosis, colitis, adhesive process, etc.

Thus, on the basis of 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 proportion of false positive results was 41%. At the same time, out of 120 patients with confirmed adenomyosis, this pathology was made a clinical diagnosis in 62.

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

The sensitivity of the method is 51.7%, the 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 a bimanual and rectovaginal examination, ultrasound of the pelvic organs, as well as hysteroscopy, were performed.

Ultrasound examination was performed in all patients admitted to the hospital. The characteristic ultrasound signs of diffuse adenomyosis were: roughness 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 (in 61%); the presence of cystic dilated cavities in the myometrium containing a finely dispersed suspension (in 45%).

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

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%, the sensitivity was 70%. The main reason for false negative results were endometrial hyperplastic processes, 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 commonly used to diagnose adenomyosis is hysteroscopy. In the course of performing diagnostic hysteroscopy, signs of adenomyosis were found in (75%) patients, namely: endometrioid passages in the form of "eyes" of a dark blue color or open, bleeding passages (in 65%); uneven relief of the walls of the uterine cavity in the form of longitudinal or transverse ridges, loose muscle fibers (in 75%); bulging of the walls of the uterine cavity of various sizes without clear contours with endometrioid passages (in 35%).

Insufficient 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.

Performing hysteroscopy after curettage of the walls of the uterine cavity is uninformative due to the development of edema and blood imbibition of the basal layer of the endometrium (Reuter K.L., 2011; Valentini A.L., 2011).

According to our data, the specificity of hysteroscopy in the diagnosis of adenomyosis was 81.2%, the sensitivity was 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 rather high accuracy of hysteroscopy in the diagnosis of adenomyosis, this method is invasive, requiring hospitalization, general anesthesia and is an operative 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; Polyzos N.P. et al., 2010).

The foregoing limits the use of hysteroscopy for the diagnosis of adenomyosis and makes it relevant 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 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, post-genomic methods of analysis are increasingly being 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 adenomyosis patients 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 UNS).

At the mass spectra processing parameters used, 96 peaks were reproducibly detected. After studying the contribution of the areas of individual peaks to classification models, 3 peaks were identified as the most significant for diagnostics, since 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 of the "adenomyosis" and "control" groups.

As seen in fig. 2, the constructed classification model included 3 mass spectrometric peaks selected by the computer program as the most significant, with m/z values: 1589; 2671; 4333, which significantly differ 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), on average after 6 months, no such peaks were found and, in accordance with the created classification models, these patients were assigned to the control group, which confirms the specificity of these peaks specifically for adenomyosis .

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

The results of profiling patients with endometrial hyperplasia were 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 the mass spectrometric profiles of blood serum samples of patients with uterine myoma, uterine body cancer and ovarian cancer, the following values ​​were obtained:

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

Table Values ​​of the specificity of the "adenomyosis" model in relation to the mass spectrometric profiles of blood serum samples from patients with other gynecological diseases.

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

There is no unequivocal answer to the question of the relationship between the changes in peptide-protein patterns recorded in the blood serum and the pathological process under study 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 ruled out, for example, as a result of abnormalities in ex vivo blood coagulation processes caused by pathology when obtaining serum from it ( Polanski M. et al., 2006; Liotta L.A. et al., 2006; Liu H. et al., 2008).

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 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 allows only 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).

The current methods for determining the functional activity of adenomyosis are mainly based on the severity of a particular 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 in order to assess the severity and prognosis of the course of the disease, it is advisable to determine the concentration as pro-inflammatory (IL-1, IL-2, IL-6, IL- 8, TNF, IF) and anti-inflammatory (IL-10) cytokines in dynamics. 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.

Given the literature data that under various pathological conditions, activation of cytokines, growth factors and the proteolysis system is observed, 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 revealed the 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 adenomyosis activity, which made it possible to predict the course of the disease.

In our study, it was found that in clinically active adenomyosis, the production of pro-inflammatory cytokines (IL-6), anti-inflammatory cytokines (IL-10), growth factors EGF, VEGF, i.e. there is an activation of the processes of proliferation and neoangiogenesis.

Conducted enzyme-linked immunosorbent assay of cytokines (IL-6, IL-10, IL-8, IL-1, IL-2, TNF, IF) and growth factors (EGF, VEFR) 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, 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 in the study of 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 on the basis of competitive interactions that can cause one or another reaction of the immune system. According to L.V. Adamyan et al. (2007) the most significant violations 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 related to adenomyosis were conducted in patients with a combination of this pathology and uterine fibroids, endometrial hyperplastic processes, etc.

Perhaps this explains our results - no changes in the concentration of IL-8, IL-1, IL-2, TNF, IF in the blood serum of 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 was found that there are two populations of CD4+ Th-cells that differ in the set of cytokines they synthesize, and this profile determines which of the two main types of immune response will be realized.

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

Our results of 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 producing IL-6 and IL -10 play a significant role in the development of immune responses in adenomyosis. Most likely, they play the main protective role in the body against this pathology.

According to the results of our study, the average concentrations in 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 were significantly higher (p

The mean values ​​of IL-6, IL-10, EGF, VEGF in patients with "active" adenomyosis were significantly higher compared with patients with "inactive" adenomyosis (p

When analyzing the content of IL-6, IL-10, VEGF and EGF in blood serum in 36 patients with adenomyosis 6 months after removal of the uterine body, 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 performed statistical analysis allowed us to reliably distinguish between two groups with "active" and "inactive" adenomyosis.

Immunological parameters above the threshold concentrations prevail in patients with "active" adenomyosis, and below the threshold - significantly more common in patients with "inactive" adenomyosis, which is statistically significant (p

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

Table Average values ​​of the studied parameters in the 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, III group 69.72 ± 3.01 66.54 ± 3, (n=50) Significance 1-2.3 *** 2-3 *** differences (p) Notes: *** denotes significance level p

The proportion of patients with a serum IL-10 level of more than 250 pg/ml was 82.5% in the group with "active" adenomyosis, and 84.8% with a level of less than 2 pg/ml 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 of more than 200 pg/ml was 81.0% in the group with "active" adenomyosis, and 84.3% with a level of less than 2 pg/ml in the group with "inactive" adenomyosis.

The results obtained indicate that the identified 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 studied immunological parameters 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, the 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 Russian doctrine of endometriosis - Professor V.P. Baskakov - “only patients with clinically active adenomyosis should be treated, and the use of hormonal drugs in patients with mild clinical activity and at the initial stages of the disease can, on the contrary, contribute to the progression adenomyosis”, determining the degree of activity is considered an important step in choosing the tactics of managing patients with adenomyosis.

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

Thus, the analysis of the information content of the studied parameters, determined in the groups of patients with "active" and "inactive" form of adenomyosis, indicates that the values ​​of IL-6, IL-10, EGF, VEGF exceeding the threshold values ​​(300 pg/ml, 250 pg/mL, 300 pg/mL and 2 pg/mL, respectively) may be used as risk factors for the progression of adenomyosis. These results confirm the expediency of measuring the concentrations of IL-6, IL-10, EGF, VEGF in blood plasma and using the obtained 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 prevalence and activity of the course of adenomyosis. According to a number of authors, the use of antiangiogenic drugs currently used in cancer patients will most effectively influence the pathological process in adenomyosis. This direction can be very promising when creating 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 (2, 4 subtypes) interact with endogenous ligands during various destruction in organs and tissues (Klyushnik T.P., 2010).

Therefore, there is reason to believe that in 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 cleaves 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, the activation of angiogenesis, and metastasis.

A 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, the activity of LE 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 range.

This may confirm 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. The activity range of 201-250 nmol/(minml) is interpreted as a slight increase, and the range of 251-300 nmol/(minml) is interpreted 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 a low concentration) of factors that cause neutrophil activation. Such a 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 severe 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 in them. The localization of this process can be established with a more thorough clinical examination of the patient and additional biochemical analyzes.

A weak and 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. The content of LE in the blood serum of patients with adenomyosis With a pronounced increase in the activity of LE, 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 result, with the severity of clinical symptoms.

Such an 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 system of proteolysis and angiogenesis 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-communicable diseases, other signs of activation of nonspecific immunity were also revealed, such as a change in the activity of the 1-proteinase inhibitor (1-PI) synthesized in the liver and an increase in the concentration of pro-inflammatory cytokines in the blood serum. The activity of 1-PI is normally 28-IU/ml.

nmol /(min * ml) Activity of leukocyte elastase, Parallel with LE, an increase in the activity of 1-PI, aimed at limiting destructive reactions, characterizes the preservation of the antiproteolytic potential; reduced activity of 1-PI 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 reflect the degree of activation of certain reactions of innate immunity, as well as the state of the antiproteolytic (compensatory potential).

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

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

It was shown that in cases where the 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 proceeded significantly more actively. On the other hand, when 1-PI values ​​are higher than the norm (more than 32 IU/ml), against the background of increased LE, there is a reserve of antiproteolytic potential that blocks the physiological effects of elastase and other proteases - in these patients, the course of adenomyosis was less aggressive and 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 uterine body, in 31 (86.1%) patients, these indicators did not exceed the standard values, which indicates the relationship between adenomyosis and disorders in the innate immunity 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) were significantly differentiating between two groups with "active" and "inactive" adenomyosis.

The studied parameters above the threshold concentrations prevail in patients in the group with "inactive" adenomyosis, and below the threshold they 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 the level of 1-PI less than 35 IU / ml - 87.1% in the group with "active" adenomyosis (p

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

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

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

In parallel with this, in the group of patients with "active" adenomyosis, the reserve of antiproteolytic potential is significantly lacking, 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 makes it possible to assess the activity of a pathological destructive process in the myometrium (adenomyosis), to clarify the severity of the disease, as well as the severity of the compensatory potential. This can contribute to the timely appointment of adequate methods of therapy, as well as the evaluation of its effectiveness.

This study opens the way for the most effective pathogenetic treatment of adenomyosis with the help of exogenous protease inhibitors, as well as hepatoprotectors in order to increase the synthesis of 1-PI.

Activity 1PI, IE / ml Today, there is a drug "Eglin-S" isolated from Hirudo medicinalis 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 today receives 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 Anamnesis data Gynecological examination Ultrasound of the pelvic organs Special diagnostic methods Blood serum profiling using stage I: MALDI mass spectrometry Prakt. Myoma Adenomyosis Cancer of the body Cancer of the uterus of the uterus of the ovaries Stage II: Definition Definition of cytokines: IL-6,10 growth factors:

(pcg/ml) VEGF, EGF (pcg/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 diagnostics - 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 forecasting, reliable verification of the process and its activity.

2. Existing postgenomic 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 body cancer - 90.5%, ovarian cancer - 100%.

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

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

Threshold values ​​for vascular endothelial growth factor are 300 pg/ml, for epidermal growth factor - 2 pg/ml: excess of these concentrations is a manifestation of the active course of adenomyosis. The diagnostic accuracy is 86%.

6. Type 1 T-helpers are not directly involved in the pathogenesis of adenomyosis, while type 2 T-helpers synthesizing 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 1-proteinase inhibitor are important diagnostic and prognostic markers in adenomyosis. The level of 1-proteinase inhibitor in the blood serum characterizes the severity of the compensatory (antiproteolytic) potential and determines the prognosis of the disease. The threshold concentration for the 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 process activity (with an accuracy of 86%), predict (with an accuracy of 89%) and evaluate the effectiveness of the treatment of adenomyosis.

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

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

3. Determination of indicators of the innate immunity 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 the choice of tactics for managing patients.

4. The use of the proposed diagnostic algorithm is advisable not only from a clinical point of view, but also from an economic one, 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 areas.

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 standpoint of evidence-based medicine // Bulletin of RUDN University, Series Medicine Obstetrics and Gynecology. - 2009. - No. 5. – S. 197-207.

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

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

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

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

Immunological determinants of adenomyosis from the standpoint of evidence-based medicine // Bulletin of the Peoples' Friendship University of Russia, Series Medicine Obstetrics and Gynecology. - 2010. - No. 6. – S. 138-145.

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

Potential proteomic markers of adenomyosis in blood serum. Vrach. - 2010. - No. 1. – P. 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. Vrach. - 2010. - No. 8. – S. 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. - P. 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 // Proceedings of the IV Regional Scientific Forum "Mother and Child" June 28-30, 2010, Yekaterinburg, C.273.

10. Sorokina A.V., Radzinsky V.E., Morozov S.G. The role of growth factors and cytokines in the diagnosis of adenomyosis // Proceedings of the XI All-Russian Scientific Forum "Mother and Child", 28.09-1.10.2010, Moscow, Russia, P.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. N.I. Pirogov. - 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 uterine diseases in blood serum // Obstetrics and Gynecology. - 2011. - No. 3. - S.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 cancer of the uterine body // 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 // Proceedings of the All-Russian Conference with international participation on gynecological endocrinology and menopause "Hormonally 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. - S. 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. - P. 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 // Vestnik RUDN University, Series Medicine, Obstetrics and Gynecology. – 2011.

- No. 6. - S. 25-29.

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

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

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

Endometriosis: new horizons of hormone modulating therapy // Dr. 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 Peoples' Friendship University of Russia, 2011. - 62 p.

Pathogenesis, prognosis and post-genomic diagnosis of adenomyosis SOROKINA ANNA VLADIMIROVNA (Russia) The paper proposes to use a non-invasive two-stage approach to the early diagnosis of adenomyosis. 120 patients diagnosed with adenomyosis of varying severity were examined, 50 practically healthy patients made up 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 allows to differentiate adenomyosis from other benign and malignant gynecological diseases - uterine myoma, uterine body 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 enzyme immunoassay, which made it possible to identify active forms of adenomyosis and thereby determine the prognosis of the course of the disease.

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

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

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

The data obtained are important for determining the prognosis of the disease and clarifying the tactics of managing patients.

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 the control group was found activation 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.