Based on clinical data, case histories, ultrasound studies, hormonal status, steroid hormone receptor levels, and estrogen metabolic enzyme activities, which are of the greatest informative value, the authors have determined a regression function for assessing a risk for endometrial cancer (EC) in patients with endometrial hyperplastic processes and calculating an individual risk. The application of this model could make an objective assessment of EC progress in these patients and use a treatment option on an individual basis. In patients with endometrial hyperplasia, the sensitivity of the EC risk prediction model was 87.5%; its specificity was 90%; these were 80 and 85.7 in the perimenopause and 92 and 83% in the postmenopause, respectively. For patients with endometrial hyperplasia con- current with uterine myoma, these indices were 87 and 85%, respectively.The mathematical model makes it possible to objectively assess the risk of EC in patient with endometrial hyperplasia in different age groups, to make up increased cancer risk groups, and to plan an individual treatment option, by taking into account both the tradi- tional indicators and the specific features of estrogen reception and metabolism.

We conducted a comparative investigation of the hormonal status (LH, FSH, estradiol, progesterone, testosterone, prolactin, SHBG), energy status (leptin, ghrelin, insulin), and carbohydrate and lipid metabolism in patients with endometrial hyperplasia and neoplasia (168 patients) with or without metabolic syndrome in the background. Patients with metabolic syndrome had a high frequency of elevated estrogen (72%), testosterone (65%), insulin (81%), leptin (68%). There was a marked increase in the basal level of luteinizing hormone, prolactin, index, LH/FSH, but decrease in FSH and progesterone. There were significant changes in carbohydrate and lipid metabolism. The possible mechanisms for the contribution of the investigated factors to the development of the pathological processes in the endometrium are presented.

Insulin-like growth factors (IGFs) and the nuclear factor κB (NF-κB) are known to play an important role in pathogenesis of endometrial cancer. However, there is still uncertainty about their proteolytic regulation. We studied the correlation between chymotrypsin-like activity of proteasomes and IGF-I, IGF-II, and NF-κB levels in endometrial cancer tissues. The total activity of proteasomes and the 20S and 26S proteasome activities were shown to be significantly higher in malignant tumors than in the unaltered endometrium. Negative correlations were found between the proteasome activity of 26S and the p50 level of NF-κB, as well as between the 26S and 20S proteasome activities and IGF-I level. The obtained data indicate the possible proteasome regulation of growth and transcription factors. As the major pool of IGF-I is considered to be located in the extracellular space, it is likely that extracellular proteasomes also take part in the regulation of the IGF-I content. The positive correlation between the IGF-I level and PAPP-A metalloproteinase is evidence that this proteolytic enzyme is another important regulator of the level of growth factor, which ensures the proteolysis of IGF-I binding proteins and, thus, increases the concentration of IGF-I in tissues. The present data show the possibility of the proteolytic regulation of growth and nuclear factors that can play an important role in cancer pathogenesis.

A mathematical model based on principles of multifactor analysis was developed to predict clinical outcome of endometrial hyperplasia (EH) in patients with metabolic syndrome (80). Seventy-seven factors--anthropometric, clinical, anamnestic, hormono-metabolic, immunohistochemical, etc.--were included. Evaluation of the most informative indices integrated with the discriminative model showed that anthropometric (waist and hip circumference, sagittal diameter, etc.) and clinico-anamnestic (age, age of secondary sexual characters appearance, body weight at birth, suckling pattern, etc.) ones are of similar significance. A profile of hormono-metabolic parameters (cholesterol-low density lipoprotein, leptin, testosterone, progesterone and fasting glucose levels) helped identify a wide range of EH-related disorders in patients with metabolic syndrome. Consistently with the literature data, level of PTEN expression pointed to the presence of this tumor's suppressor in most EH cases which was matched by absence of its expression in endometrial carcinoma. Our model provided high sensitivity (89%) and specificity (82%) in predicting risk of progression in patients with endometrial hyperplasia and metabolic syndrome.

Multivariate analysis of data has yielded mathematical models of prognosis for endometrial cancer (EC) patients with and without metabolic syndrome (84 and 62 subjects, respectively). A total of 77 signs, including anthropometric, clinicoanamnestic, hormonal-metabolic, and immunohistochemical parameters, and the indicators of insulin-like growth factors in the endometrial tumors, were analyzed. All the patients with EC were divided into 2 groups in accordance with individual prognosis. The criteria for good prognosis were no recurrences, metastases, or death during 60 months. Analysis of the informative criteria included into the mathematical model indicated that EC patients with metabolic syndrome are typified by the fact that the formula contains values that are either direct criteria for metabolic syndrome or values closely clinically related to metabolic syndrome (insulin resistance, the level of triglycerides, and primary infertility). The specific feature of the model was an indicator, such as disease stage, for EC patients with metabolic syndrome and the histotype and differentiation degree of a tumor for those without metabolic syndrome, which seems to be associated with the fact that it is in this group that non-endometrioid tumors are much more frequently encountered. The level of PAPP-A was one of the most informative prognostic values in patients with and without metabolic syndrome.

The literature review deals with the problem of metabolic correction of hormonal-metabolic disturbances in patients with endometrial hyperplasia (EH) and endometrial cancer (EC) with the evidence of metabolic syndrome. Metabolic correction together with conventional treatment in EH patients with metabolic syndrome is expected to contribute to the reduction in the risk of EC development. The development of new methods for predicting EC outcome as well as options for metabolic rehabilitation of these patients is required.

The proteasome system has been ascertained to play a key role in the development of cancer of the kidney, urinary bladder, and endometrium, which is likely to be linked to the regulation of tissue growth factor levels. Decreased proteasome activity in a renal tissue tumor versus normal tissue is accompanied by activated neoangiogenesis, as suggested by the higher content of vascular endothelial growth factor. In bladder cancer, the activity of tumor enzymes did not differ from their activity in the adjacent tissue. In endometrial cancer tissue, that of proteasome was increased as compared with that in the normal tissue. The content of insulin-like growth factor 1 in the endometrial cancer tissue was associated with the activity of proteasome in the normal tissue.

Sex hormone profile was investigated in uterine systemic and local blood flow in endometrial hyperplasia and carcinoma. The results were compared with levels of aromatase and steroid sulfatase - estrogen metabolism enzymes. Local hyperestradiolemia and hyperestronemia were detected in cancer patients. Estradiol and estrone in endometrial hyperplasia were lower than in cancer which conforms to estrogen theory of hormonal carcinogenesis. There was no evidence for the role of hyperestrogenemia in endometrial hyperplasia development. Aromatase was a factor of intensified estrogen synthesis in altered and hyperplastic endometrium. There was an inverse correlation between intratumoral steroid sulfatase levels and those of estrone in uterine local blood flow.

Prognostic significance of sex hormones, sex hormone-binding globulin, estrogen and progesterone receptors as well as the activity of enzymes involved in estrogen synthesis (aromatase, steroid sulfatase, estrogen hydroxylase, catechol-O-methyl transferase, glutathione-S-transferase) were investigated in 74 endometrial carcinoma patients. Stage and duration of uterine myoma history appeared to be significant factors of overall survival. Such factors as stage, depth of myometrial invasion, body mass, blood-serum estradiol level as well as aromatase and catechol-O-methyl transferase concentration in tumor tissue were significant for free-relapse free survival period.