Modern problems of science and education. Adenomyosis - a latent and dangerous disease Adenomyosis scientific articles

INTRODUCTION

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

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

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

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

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

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

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

Heterotopies of internal genital endometriosis are considered as derivatives of the basal layer of the endometrium, and not functioning, as in the translocation theory of "true endometriosis". Recently, data began to appear on the commonality of endometriosis and adenomyosis, their origin, the uniformity of mechanisms that support the existence of heterotopies and their ability to progress.

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

The degree of elaboration of the research topic

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

The genes of cytochrome P450: CYP1A1 (A2455G (Ile462Val)), CYP2E1 (C9896G), CYP19 (TTTA) and del (TST) - in endometriosis were studied only in single studies [Shved N.Yu., 2006, Montgomery et al, 2008], there are no works that would assess the prognostic significance of these polymorphisms.

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

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

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

Research objectives:

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

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

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

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

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

Scientific novelty

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

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

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

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

Practical significance

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

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

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

A comprehensive system for predicting the development of adenomyosis has been developed, including a computer program based on the assessment of clinical and anamnestic data and the assessment of molecular genetic markers. The computer program "Predicting the development of adenomyosis" was developed using the logistic regression method, it allows predicting the development of the disease with a probability of 99%. The sensitivity of the program is 85.8%, the specificity is 89.9%. The information content of molecular genetic research methods has been established. It has been shown that a comprehensive determination of genetic markers of estrogen metabolism: CUR1A1, StA2, CUR 19, BSTY! - has a sensitivity of 86.7% and a specificity of 90.6% and can be used to predict the development of adenomyosis in adolescents and young women in order to form groups of increased risk for the development of the disease for preventive measures.

Putting the results into practice

On the basis of the study, the methodological recommendations “Adenomyosis: molecular genetic characteristics, risk factors and prognosis” were developed; the DOZN of the Kemerovo Region was approved (the act of implementation of March 11, 2013), introduced into the practice of medical institutions (the act of implementation of March 12, 2013) and the educational process of the departments of obstetrics and gynecology No. 12 March 2013).

Provisions for Defense:

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

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

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

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

Approbation of the dissertation material. The main points of the work were reported at the XI International Congress on Endometriosis (Montpellier, France, 2011), the XII All-Russian Scientific Forum "Mother and Child" (Moscow, Russia, 2011), the Kemerovo Regional Day of the Specialist Obstetrician-Gynecologist (Kemerovo, 2011), XVI International Scientific and Practical Conference "From Assumption - to Establishing Truth" (Russia, Kemerovo, 2012), XV World Congress on Human Reproduction (Italy, Venice, 2013), XVII International Scientific and Practical Conference "Conceptual Approaches to Solving Reproductive Problems" ( Russia, Kemerovo, 2013), discussed at the interdepartmental meeting of the departments of obstetrics and gynecology No. 1, No. 2 GBOU VPO KemSMA of the Ministry of Health.

Volume and structure of the thesis

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

1. The frequency of adenomyosis among patients undergoing hysterectomy is 33.4%, isolated adenomyosis occurs in 17.9% of cases, in combination with uterine myoma - in 31.4%, endometrial hyperplasia - in 10.4%. These patients are characterized by abundant (94.8%) and painful (48.5%) menstruation on average from 38.5 ± 0.7 years, only 10% of women receive treatment for adenomyosis, and the time interval from the onset of symptoms to surgery treatment is 12 years on average. Anamnestic features of patients with adenomyosis are a high incidence of obesity (66%), hypertension (58.5%), medical abortions in history (72.5%), IUD use (45.8%), burdened heredity for oncological diseases of the reproductive system (4.9%).

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

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

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

5. The computer program "Prediction of adenomyosis" developed using the logistic regression method allows predicting the development of adenomyosis in 99% of cases. The sensitivity of the program on an independent sample is 85.8%, the specificity is 93.3%. An isolated assessment of the polymorphisms of individual genes CYP1A1, CYP1A2, CYP 19, SubT1A1 has a sensitivity of 68.6-79.8% and a low specificity of 6.9-23.4%. A comprehensive assessment of the polymorphisms of these genes has a high sensitivity - 86.7% and specificity - 90.6% in predicting adenomyosis.

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

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

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

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

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