ВПЛИВ ОЖИРІННЯ НА РОЗВИТОК ГІПЕРПЛАЗІЇ ЕНДОМЕТРІЯ В ЖІНОК РІЗНОГО ВІК

itself as an active endocrine organ. Pathological processes occurring in adipose tissue with its hypertrophy during weight gain are considered links in carcinogenesis in more than 20% of malignant tumors, including endometrial and breast cancer. The aim of the research was to study the effect of excess weight (BMI >30) on the development of endometrial hyperplasia in women of reproductive age and in menopause. The medical histories of 62 patients from 2016 to 2018 with diagnoses of endometrial hyperplasia without atypia and endometrial hyperplasia with atypia were reviewed in a retrospective study according to pathological histology after hysteroscopy. Depending on the reproductive status and body mass index, four groups of patients were formed. Obtained data showed that in women with obesity, the percentage of atypical hyperplasia (65.9%) was significantly higher than in women with normal body weight (28.6%). In young women with overweight, the percentage of atypical hyperplasia was 57.9%, while for BMI <30 – 16.7%. In women of menopausal age with a BMI >30 percent of atypical hyperplasia, 68.2%, while with a BMI <30 – 33.3%. In women of menopausal age with a BMI >30 percent of atypical hyperplasia is 64.9%, while in young women with a BMI >30 – 48%. The results of the study show that atypical hyperplasia of the endometrium is more often detected in the presence of excessive body weight, and the risk of its development among obese women of menopausal age is comparatively higher than in obese young women. Since the probability of progression of endometrial cancer is increased 45 times within 1 year if the diagnosis of endometrial hyperplasia is confirmed histologically, weight correction is a method of preventing the development of atypical changes in the endometrium at any age.


INTRODUCTION AND ANALYSIS OF THE LITERATURE DATA
According to the National Cancer Registry of Ukraine, the proportion of malignant neoplasms of the uterus body in the structure of the incidence of the female population ranked second (10.4%) in 2016 after breast cancer (23.2%), with the exception of non-melanoma skin diseases [1]. For example, in 2012 this indicator was 9.8%, after which it remains at a stable level of 10.3-10.4%. Late detection and imperfect prediction of the endometrial adenocarcinoma development factors lead annually to a huge number of hysterectomies depriving woman of the opportunity to realize her reproductive potential.
It should be noted that removal of the uterus is a psychological test for a woman and also often causes a misunderstanding with a partner through dyspareunia (66.15%), loss of libido (30.76%), anorgasmia (29.23%) [2]. 24% of patients suffer from depressive disorders in the postoperative period and this figure is reduced only slightly to 21% a year after the operation [3]. According to the 2014 edition Classification of Tumors of the Reproductive Bodies of the WHO, the risk of developing endometrial carcinoma increases by 3-4 times in women who are exposed to "undisguised" estrogens (for various reasons), and at a persistence of this condition 10 times over 10 years [4]. Progression of simple endometrial hyperplasia in a highly differentiated endometrial carcinoma occurs in 1-3% of women. From 1/4 to 1/3 of women with atypical hyperplasia detected by biopsy results, endometrial cancer will be diagnosed after an immediate hysterectomy or during the first year of conservative management.
The uterine adenocarcinoma is divided into two types on the basis of histological, clinical and metabolic features: Type 1: endometrioid -estrogen dependent, develops against the background of endometrial hyperplasia and has a more favorable prognosis; Type 2: estrogen independent, develops against the background of postmenopausal endometrium atrophy and has a worse clinical prognosis and an unfavorable course.
Endometrial hyperplasia with atypia, or endometrial intraepithelial neoplasia (EIN) is the basis for the development of endometrioid adenocarcinoma. It is mainly characterized by an increase in the glands relative to the stroma, compared with the normal endometrium of the proliferation stage. If the diagnosis is confirmed histologically, the probability of progression of endometrial cancer increases by 45 times within 1 year [5].
The risk factors for the development of endometrial hyperplasia, both simple and atypical, are presented in the Table. It is well known that in the absence of ovulation, for example, in PCOS and in the menopausal period, estrogens convertible by 5-alpha reductase of adipose tissue stimulate proliferation and, as a result of prolonged stimulation, endometrial hyperplasia [7].
But this is not the only pathological way of the development of endometrial hyperplasia. Obesity, especially in the abdominal type, is the basis for the development of insulin resistance, hyperglycemia, dyslipidemia and pro-inflammatory condition. The epidemiological study of 2017 indicates an increase in the risk of developing adenocarcinoma by 1.54 times for every 5 kg/m 2 of body mass index (BMI) [8].
Based on these data, it is possible to make an assumption about the relationship of obesity with the precursor of adenocarcinoma -atypical hyperplasia of the endometrium.

THE AIM OF THE STUDY
Excessive accumulation of adipose tissue is not only a matter of aesthetics or fashion and features of different cultures. Diseases associated with obesity are the main cause of morbidity and mortality which could be prevented by modifying this unfavorable factor. It has been proven that overweight is associated with 20% of cancers, such as breast, colon, prostate cancer.
Fatty tissue, which was previously considered a passive depot of metabolism, is now recognized as an active endocrine organ. It is heterogeneous in histological structure -it consists of half of mature adipocytes and half of preadipocytes, fibroblasts, nerve and endothelial cells and macrophages. White fatty tissue secrets a wide profile of biologically active substances, called adipocytokines, which play the role of mediators of some obesity-associated diseases.
The presence of preadipocytes (1 in 50 mature adipocytes) that are stem cells is important. When the preadipocyte is divided under certain conditions, new fat cells arise that will function as long as a person exists. They may decrease in volume, but not in numbers.
The highest concentration of preadipocytes in adipose tissue is observed in certain periods of life, when their active reproduction occurs -the second half of pregnancy, the first year after birth, puberty. During these periods the body is particularly susceptible to obesity and the development of leptinoresistance and hyperleptinemia. While weight gain, there is a qualitatively different process -hypertrophy of adipose tissue. Adipocytes while accumulating lipids can increase by 20 times from their initial diameter and several hundreds of times from the original volume. This is the reason for a quick weight gain in case of a disturbance of diet -when losing weight, the number of fat cells does not decrease, only their volume and lipid content change.
When the adipocyte reaches its limit of volume, hypoxia and necrosis occur, which triggers chronic subclinical inflammation. These processes are the primary links of carcinogenesis, tumor progression and metastasis.
The hypoxia-induced factor 1 alpha (HIF-1a) is involved in the stimulation of the transcription of genes that play a role in carcinogenesis and is a factor that stimulates vascularization of tumors and is associated with the incidence of metastasis by: 1. Inhibition of the synthesis of adiponectin. 2. Induction of insulin resistance. 3. Products of angiogenic factors. 4. Releasing proinflammatory cytokines. 5. Hyperproduction of free radicals and damage to the DNA of adipocytes.
Thus, hypoxia of adipocytes in obesity is a key link between primary damage and activation of inflammation.
While most of the adipose tissue cytokines are proinflammatory, adiponectin has anti-inflammatory, cardioprotective, antitumor and antidiabetic effects. Adiponectin is produced by a mature, not hypertrophied fatty tissue. Adiponectin levels decrease with obesity in the abdomen in men, postmenopausal women, at high arterial pressure, coronary heart disease and hypertriglyceridemia in type II diabetes mellitus.
Adiponectin inhibits the proliferation of adipocytes, endothelium and tumors by inducing apoptosis [6]. The higher the plasma adiponectin level, the lower the risk of developing endometrial cancer, colorectal cancer, breast and pancreatic cancer, prostate, while at low concentrations this risk increases.
The second factor in the development of endometrial hyperplasia is the leptin hormone, which plays the role of a regulator of body weight. He signals the hypothalamus about a decrease in appetite. The production of this hormone is closely related to the amount of fat in the body (especially visceral), as well as a high-calorie diet. With the introduction of fats into the body and weight gain, the level of leptin increases, which is aimed at preventing hypertrophy of adipocytes, protecting them from death from excessive stretching. Under conditions of obesity, a state of leptin resistance develops, so the physiological effect of this hormone is not realized.
At the moment, leptin is in the center of obesity-cancer connection, since it is produced in proportion to the mass of body fat and potentiates mitogenesis, growth and cell activity.
Mature adipocytes produce both adiponectin and leptin, whereas pre-adipocytes produce only leptin, in addition, in high concentrations. Accordingly, the increase in preadipocyte pool in obese people is directly related to the increase in leptin secretion, which stimulates the differentiation of monocytes into macrophages, causing a state of chronic inflammation.
Since, according to the latest report of the Organization for Economic Cooperation and Development of 2017, overweight, despite the popularization of a healthy lifestyle, is inherent in 20.10% (6,005,282 obese) of the Ukrainian population, there is a need to investigate the relationship between obesity (BMI <30) and the risk the development of endometrial hyperplasia in women of reproductive age and in menopause.

MATERIALS AND METHODS OF THE STUDY
The medical history of 62 patients from 2016 to 2018 with diagnoses of endometrial hyperplasia without atypia and endometrial hyperplasia with atypia was recursively analyzed according to the pathohistological study. Endometrial specimens were obtained by hysteroscopy. Depending on the reproductive status and BMI, we identified four groups of patients: I. women of reproductive age with BMI <30; II. women of reproductive age with BMI >30; III. menopausal women with BMI <30; IV. menopausal women with BMI >30. In each group the percentage of endometrial hyperplasia with atypia was calculated.

RESULTS OF THE STUDY AND DISCUSSION
The data obtained from the study show that according to histology results, in obese women, the percentage of atypical hyperplasia was significantly higher than in women with normal body mass (65.9% for women with BMI >30 and 28.6% for women with BMI <30 in accordance). In young obese women, the percentage of atypical hyperplasia was 57.9%, while BMI <30 -16.7% (Picture 1).
In our view, based on the result obtained, it is advisable to study the prospects of laboratory testing for fat tissue factors (leptin and adiponectin) in order to predict the risk of endometrial proliferative changes in women with BMI >30.
In a study 2017, women who lost 30.15 kg via bariatric surgery levels of C-peptide, insulin, leptin, IL-1Rα and IL-6 decreased, while sex-binding globulin, IGFBP1 and adiponectin normalized [10]. This means that the risk of atypical hyperplasia of the endometrium and adenocarcinoma can be reduced by using modern surgical techniques.
It is important to note that the positive result in the correction of dyslipidemia and hyperinsulinemia is also demonstrated by some compounds, namely D-chyro-inositol, belonging to the vitamin B family, and is an active ingredient of the preparation Protalis. D-chyro-inositol promotes transport of glucose inside the cell and has a high safety profile. In our clinic, we have an extensive experience in the use of Protalis for the treatment of women with PCOS and insulin resistance, menstrual irregularities and infertility, and we see perspectives for use with excess weight and, as a consequence, recurrent endometrial hyperplasia.
After all, the prevention of the development of hyperplasia of the endometrium, especially atypical, significantly reduces the incidence of endometrioid adenocarcinoma.

СONCLUSIONS
1. Based on the results obtained, we can conclude that atypical hyperplasia of the endometrium is more often found in the following groups of women: overweight women of any age; women of reproductive age with BMI >30; menopausal women with BMI >30.
Menopausal women with obesity are more vulnerable to the development of atypical hyperplasia than obese young women.
2. Thus, it can be argued that obesity is a risk factor for the development of atypical changes in the endometrium, which is independent of age and reproductive status, but can be modified by using a variety of available and safe methods for weight loss.
3. Since, according to various authors, the probability of occurrence of adenocarcinoma in such conditions is increased 45 times over 1 year, there is an urgent need for counseling women for a healthy lifestyle. In overweight women, attention should be paid to the diagnosis of metabolic syndrome, insulin resistance, PCOS, and the prevention and treatment of obesity and related obesity.