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73 randomly selected from the entire array menopausal endometrial cancer patients (34 of whom were subjected to further surgery by laparotomy and 39 - by laparoscopic ap- proach) were examined 48-72 hours before surgery. Patients passed anthropometry, their medical history was collected, and in the blood serum, taken on an empty stomach, glucose, gly- cated hemoglobin, lipid fractions, insulin, thyrotropin, estradiol and testosterone levels were measured while insulin resistance index was calculated. Although patients who later went through laparoscopic surgery were characterized by somewhat higher body mass and waist circumference, other investigated pa- rameters did not differ between laparoscopy and laparotomy groups. Moreover a frequency of so called "metabolically healthy" obesity appeared to be even higher in laparoscopic group. Taken together this confirms the fact that the overweight should not be considered as contraindication for videosurgery in patients with endometrial cancer. At the same time it is desirable to compare distant oncological results with individual characteristics of pre-surgical hormonal-metabolic status of pa- tients depending on the surgery type and obesity phenotype.

Mammographic breast density (MBD) was determined visually in 51 postmenopausal women examined in the fasting state and after oral glucose level for obtaining their anthropometric and laboratory characteristics. The women presenting with impaired glucose tolerance/newly diagnosed diabetes mellitus (n=16) had the same MBD values as those having no such disorders (n=35). In the presence of the symptoms of metabolic syndrome, mammographic breast density tended to decrease to 16.5±4.3% in 17 women compared with 24.4±3.1% in 34 women without such symptoms. The diabetes risk score, unlike the blood glucose and reactive insulin levels, showed negative correlation with the MBD values. Such inverse relationship was especially pronounced in the women with the disturbances of carbohydrate metabolism and symptoms of metabolic syndrome. The inverse correlation between these characteristics and MBD values showed the strong dependence on the body mass index. It is concluded that parameters associated with impaired glucose tolerance and metabolic syndrome considered to be risk factors of the development of breast cancer are unrelated to increased mammographic breast density which suggests the difference in the mechanisms responsible for hormonal and metabolic predisposition to these pathologies.

It is shown that endometrial cancer features (including expression of the PTEN and HER-2/neu proteins) are connected dissimilarly with body mass index and with the belonging of the patients to the groups with standard, SO and metabolically healthy obesity, MHO. In the course of the last half-century an increases are discovered in the height and weight of the females with endometrial cancer that moves in the opposite direction with a reduction of the share of MHO cases among obese patients. This conclusion should be taken into account when one considers the means for contemporary prevention of both obesity and cancer of uterine body.

The effect of the biguanide siofor (metformin) on the menstrual function of the endometrium and on hormonal and metabolic parameters was studied in 27 patients with ovarian polycystosis (OPC), of them 15 patients (mean age 30.7±1.7 years) were treated with the antidiabetic biguanide siofor (Berlin-Chemi) for 3 months. Siofor (metformin) used alone in patients with OPC was effective in restoring a regular menstrual cycle in 60% of cases and concurrently showed a moderate decrease in body weight. There was a significant reduction in the blood level of luteinizing hormone (LH) in most siofor-treated patients with OPC (more frequently in obese patients), which is indicative of that it is important to correct the states of central parts of the reproductive system, which are involved (along with insulin resistance and impaired steroidogenesis) in the development and formation of a clinical picture of the disease. The elevated concentration of C-peptide was found in the blood, which might be one of the manifestations of overcoming insulin resistance.

The state of the viscosity of erythrocyte membranes in breast cancer patients (68--in menopause and 32--with menstrual cycle) was studied in comparison with the content of steroid hormone receptors in the tumor tissue and the age of patients. It is showed that the less hormone dependence of the tumor the higher viscosity of erythrocyte membranes that manifested by a decrease in the coefficient of eximerization (CE) of pyrene in the protein/lipid and in particular, lipid/lipid membrane layers. Increasing CE of pyrene in lipid/lipid layer of erythrocyte membranes above 1.7 units, reflecting a decline in their microviscosity, could be considered as an additional extra-tumor criterion for identification of the tumor as of hormone dependent type.

Female rats (aged three months at the start of the study) were kept for four months on drinking water (group 1) or 5% ethanol. Rats drinking ethanol were additionally divided into six groups (groups 2–7). During the next two months of the experiment, animals of group 2 continued to drink only ethanol, while rats of group 3 additionally received N-acetylcysteine, those of group 4 received ascorbic acid (vitamin C) and α-tocopherol (vitamin E), those of group 5 received melatonin, those of group 6 received carnosine, and those of group 7 swam in the so-called training regime for five days a week. All animals underwent bilateral ovariectomy 2.5 weeks before experiments ended, and were given daily i.m. estradiol (2 μg) during the 11 days before the last experimental day. After treatments, blood estradiol and cholesterol levels were measured, along with progesterone receptor levels, peroxidase activity, the index of proliferation, the proportions of cells in the S and G2/M phases, the thickness of the endometrium, and the extent of DNA damage (using the “comet” technique) in uterine tissue. Liver estradiol 2-hydroxylase activity was also measured. The results led to the conclusion that drinking of 5% ethanol in combination with administration of estrogens was accompanied by induction of genotoxic (G) changes in the uterus and that this was prevented by administration of N-acetylcysteine and melatonin. The combination of vitamins C and E increased some of the manifestations of the hormonal (H) effect of estrogens (uterine weight and induction of progesterone receptors), but weakened others (the index of proliferation). As a result, the combination of N-acetylcysteine and optimum doses of ascorbic acid and α-tocopherol can be recommended for preventing the estrogen effect-switching phenomenon (increases in the G component on the background of weakening of the H component), which is seen particularly in patients consuming excessive amounts of alcohol, increasing the risk that the genotoxic version of hormonal cancerogenesis will develop.

We studied the influence of various methods for correction of age-related changes (administration of N-acetyl-L-cysteine, vitamins C and E, melatonin, and carnosine and swimming training) on the realization of estrogens effects in ovariectomized rats. The proliferation index in the endometrium decreased in 12-14-month-old control animals. The weight of the uterus, percentage of "comets", and average length of their tail in estradiol-treated rats far surpassed the corresponding parameters in control animals. Administration of melatonin and N-acetyl-L-cysteine and swimming training corrected these genotoxic abnormalities. Our results indicate that aging induces incomplete variant of the phenomenon for switching of estrogen's effects (increase in the severity of genotoxic damage without facilitation of the hormonal effect). These methods for correction of age-related changes have not only common, but also distinguishing characteristics compared to correction of changed induced by drinking of ethanol in various concentrations, whole body γ-irradiation, and exposure to tobacco smoke.

Preliminary data are confirmed on the more rare prevalence of family history of diabetes mellitus (DM) in cancer patients, mainly females, with diabetes in comparison with diabetics without cancer pathology. Familial diabetes does not worsen additionally tumor characteristics against the same in patients with non-familial diabetes. More than that, familial diabetes in diabetics with breast cancer goes together with lesser size of tumor and demonstrates an inclination to the rarer distant metastases in breast and endometrial cancer patients. The signs of systemic DNA damage (evaluated, in particular, on the basis of 8-OH-dG serum levels) are pronounced in postmenopausal diabetic cancer patients with familial diabetes in lesser degree than in non-familial variant of DM. In toto, this allows to consider family history of DM in patients with type-2 diabetes as a particular factor of tumor growth containment, which mechanisms and causes, warrant further studies.

High level of thyroglobulin (Tg) after thyroidectomy has been shown to be an early marker of either metastases or local recurrence of differentiated thyroid cancer (DTC). The aim of this study was to evaluate the relation between Tg level estimated on the third week after thyroidectomy and clinic-pathologic characteristics of DTC as a possible prognostic criterion used to mark the patients with radioiodine therapy indications. Research data on 45 patients (39 women, 6 men, age 22-75 years) with DTC and without high level of Tg autoantibodies have been included in the study. Eleven patients underwent surgical treatment due to disease recurrence. In all patients Tg and thyroid hormones levels were measured before the thyroidectomy and on the third week after it. The postoperative level of Tg as TTM coefficient (ratio of postoperative Tg to daily L-thyroxin dose in mcg to body weight in kg) was higher in patients with unfavorable prognosis: (a) capsular invasion, (b) cervical lymph nodes metastases, (c) advanced disease stage, (d) high risk of recurrence. The postoperative serum Tg levels were similar in primary disease patients and patients with DTC recurrence. There was no relation between preoperative Tg level and any prognostic factors although there was a tendency to higher (more than 2 ng/ml) Tg levels in patents with high preoperative Tg levels. Finally, the serum Tg level on the third week after thyroidectomy is a valuable prognostic criterion and can be used in DTC to determine the radioiodine therapy indications.

Of examined 37 breast cancer patients (average age 42,3 +/- 1,2 years) 25 had not had any specific therapy by the date of investigation and the rest 12 had received in average 5,3 +/- 0,6 cycles of neoadjuvant chemotherapy mainly TAC and FAC. It was revealed that such kind of treatment conformed to valid decrease of both testosterone level and ratio value [(testosterone concentration/follicle stimulating hormone concentration, FSH) x 100] in blood serum. Testosterone level in blood of patients in fact decreased to similar values both in amenorrhea induced by adjuvant chemotherapy and saving menorrhea. This is a confirmation that maintenance of menorrhea does not mean intactness of ovarian function (ovarian reserve) and indicates that evaluation of testosteronemia in these circumstance at least does not give in estimation of estradiol and FSH's content in blood. Further attention could be paid to study testosteronemia before and after neoadjuvant chemotherapy as a potential additional prognostic factor of efficacy of this treatment for breast cancer patients.

Mammographic breast density (MBD) value is currently one of the strong predictors for mammary carcinoma development. There are also other conditions predisposing to MBD increase with hormone-related markers different from those used in breast cancer, while pharmacological methods for MBD reduction are few and still considered experimental. In the current study 25 postmenopausal women received daily for a median 10.5 months 1-1.5 g of antidiabetic biguanide metformin (siofor) (n = 14) or 400-600 mg of antigenotoxic drug N-acetylcysteine (n = 11). In both groups MBD was measured before and after treatment. The effects of both drugs were quite similar. Metformin use lead to lower MBD in 4 of 14 (28.5%) women with mean MBD decrease of -1,24% (absolute dynamics) and -5.03% (relative value). In N-acetylcysteine group this effect was observed in 27.3% of cases, with -2.0% absolute dynamics and -6.1% relative dynamics. In metformin group the most evident absolute and relative dynamics was observed in patients with no signs of metabolic syndrome, -10.86% compared to -2.45%. In 7 women the metformin use also lead to decrease of dense and increase of non-dense areas on digital scans, leading to decrease in dense to non-dense area volume ratio. Therefore, the similar effects of metformin and N-acetylcysteine are probably explained mostly not by insulin resistance elimination by metformin, but by altered cell proliferation, apoptosis and DNA repair.

Our study involved 25 postmenopausal patients (endometrial carcinoma--16, breast (6) and colorectal (3) cancer, aged 56.8 +/- 0.9). All patients were in clinical remission. None had received any specific therapy for at least 12 months. After a laboratory endocrine-genotoxic switch evaluation, 17 patients were given an antidiabetic drug--biguanide metformin--or N-acetylcysteine as antioxidant (8) for 3 months. A checkup was carried out on completion of the course. As a result, hormonal and progenotoxic effects of glucose were found to be inhibited significantly. Much less pronounced was the impact on relevant effects of estradiol which were investigated vis-a-vis nature of blood mononuclear response in vitro. Both isolated and combined administration of said drugs used for endocrine-metabolic rehabilitation is justified.

Poly(ADP-ribosyl)ation polymerase-1 (PARP-1) is a major factor of DNA repair. Age-related parameters such as body weight and blood cholesterol in knockout male mice PARP-1 were more pronounced as compared with controls. Mean life span was shorter (486 +/- 31.7 and 723 +/- 22.6 days, respectively, (p = 0.000005) while initial risk of death (beta) was 8 times as high as in mice PARP-1(+/+). Mean latency of all tumors in knockout and control mice was 656 +/- 43.5 and 782 +/- 33.8 days, respectively, (p0.05). Among the most frequent neoplasms were tumors of the liver (experimental--22% and control--8%, respectively) (p = 0.03) and lungs (8% and 12%, respectively). Hence, mice PARP-1(-/-) revealed certain typical charhacteristics of accelerated aging, shorter life span, earlier carcinogenesis and higher rates of liver tumor incidence as compared with mice PARP-1(+/+). Our evidence highlights the role of DNA repair in carcinogenesis and aging.

A relationship was studied between generation of glucose-induced reactive oxygen species capable of causing damage to DNA (genotoxic or G-effect) and insulin secretion (endocrine or hormonal effect - H-effect) in primary menopausal patients with endomrnetrial carcinoma (EC) (32) or colonic cancer (CC) (16). The study group was compared with healthy menopausal women (25) and patients with an impaired glucose tolerance (IGT) (21). Besides, we examined 32 menopausal patients (CC--6 and EC--26) more than 12 months after surgery. The following basic patterns were established: (1) H-effect was reported in EC-1 and 1GT groups nmore often than in healthy peers and those with EC-2: (2) G-effect tended to prevail in CC patients and those with EC-2 and in patients with EC-1 twelve months after operation; (3) G-effect occurred more often in primary EC patients, particularly, those with EC-2 (71%) and IGT (58%) (as compared with CC patients (33%) and healthy females (por = 0.001). It is suggested that a comparison of the two effects might provide a criterion for use of relevant means of prevention of certain malignancies or correction of disorders in cancer patients following radical treatment.

Twenty-four patients with thyroid carcinoma receiving thyroxine were examined. The thyroid gland had been extirpated in 20; hemithyreoidectomy (4). Tests with ethinyl estradiol (50 mcg, per os, 6 days) (8), estradiol valerate (2 mg, per os, 12 days) (10), and tamoxifen (40 mg, per os, 14 days) (6) were carried out on the assumption of normal and neoplastic thyroid epithelium sensitivity to estrogen stimulation. Blood thyroglobulin, TSH and estradiol levels were assayed before and after loading. Thyroglobulin concentrations increased in 5 out of 24 patients (ethinyl estradiol--1 out of 8, estradiol valerate--2 out of 10 and tamoxifen--2 out of 6); those of TSH--in 6 out 24 (3 out of 8, 2 out of 10 and 1 out of 6, respectively). Enhanced thyroglobulin correlated with higher levels of TSH in 2 out of 5 and with blood-estradiol--in 4 out of 5. It was suggested that at least, in some patients, the preparations might produce a direct stimulating effect on thyroglobulin biosynthesis in the thyroid tissue remnants. Further research is suggested or on whether tamoxifen exerts pro- or antiestrogenic influence on thyroid epithelium.

Our investigation included 158 women, aged 23-73: patients with tumors of the ovary, breast and endometrium--117 and subjects without oncological pathology--41. Autoantibodies to microsomal fraction of follicular ovarian cells (500 Unit/ml) in healthy subjects were revealed 8.3% while in patients with ovarian, breast and endometrial malignancies (without significant differences between benign and malignant tumors) in 33.30%, 45.60% and 25.0%, respectively. Higher level of anti-ovarian autoantibodies involved an inverse correlation between blood levels of FSH and estradiol in ovarian and endometrial carcinoma patients. It also co-occurred with a tendency of increasing levels of autoantibodies to thyroglobulin. Whatever apparent predictive accuracy in oncological clinic, high concentrations of anti-ovarian autoantibodies point to certain shifts taking place in the formation of reproductive system pathology. Besides, they may have considerable prognostic significance.

Relation was studied between generation of glucose-induced reactive oxygen species (ROS), which appear to be related to DNA damage (genotoxic effect, G), and insulin secretion (endocrine or hormonal effect, H) in women of different ages (one group under 45 and the other one over 45; n=25 and n=14, respectively). The healthy women in those two groups were compared with patients in whom we had found an impaired glucose tolerance (IGT) or type 2 diabetes mellitus (DM) (n=17, mean age 57.3 +/- 2.7). The hormonal effect of glucose was more pronounced in the senior group, and especially in group with IGT, if compared with the younger group. Genotoxic effect of glucose was discovered more frequently in the younger group, mainly in smoking women. Comparison of G/H effects showed that the evaluation of glucose-induced genotoxity (GIGT) was more frequent in the IGT group than in the senior group (p0.05). No difference was detected in the GIGT frequency values in the two healthy groups. It may therefore be concluded that GIGT did not increase within the ambit of ageing studied in this work, while it increased in the IGT group. It is possible that the high frequency of the G effect in the IGT group could be a marker of oxidative stress and/or predisposition to complications in DM. The dual (joker) function of glucose and the prevalence of G effects over H effects may be of use in choosing the method of correction for each particular case.

Gail coefficient (GC) generally used in breast cancer predictions for the next 5 year--or entire survival was determined in both patients and healthy controls of the same age, residents of St. Petersburg. Simultaneously, a correlation was established with hormono-metabolic indices, receptor pattern, tumor stage and size and some other characteristics. GC in cancer patients with age50 was significantly higher than in control. In menopausal cancer patients, greater GC correlated with such parameters as body mass, weight index, glucose, total cholesterol and low density lipoproteids after fasting. The latter group showed a tendency towards enhanced estradiol and testosterone in blood serum. In reproductive patients with elevated GC, estradiol level rise was significantly lower and most tumors were receptor-negative. However, involvement of regional nodes was relatively rare. To summarize, GC determination characterizes risk and certain clinico-morphological features of distinction between reproductive and menopausal patients.

Peculiarities of the incidence and spread of main non-infectious diseases (MNID) are in one or another way connected with the conception of "normal" and "successful" aging. The age-related increase in the frequency of MNID, associated with estrogen deficiency or excess, can be explained by the presence of estrogen effect switching phenomenon. The increase in the genotoxic effect of estrogens, isolated or combined with the weakening of the hormonal effect, can worsen the clinical course of MNID (including malignant tumors of hormone-dependent tissues). The effects of two other endocrine-genotoxic switchings (the joker function of glucose and adipogenotoxicosis) may realize in the same direction. The three mentioned phenomena form the so called basic triad, separate elements of which can interact. Endocrine-genotoxic switchings and their inductors are targets for prophylactic measures and, possibly, therapeutic ones. Both approaches may be divided into several groups with different points of application, whereas their ultimate goal is optimal balance between hormonal and DNA-damaging effects of estrogens, glucose, and adipose tissue-associated factors.

Breast cancer course may be influenced by a profile of steroids and peptides produced by mammary fat. The study was concerned with assessment of hormonal (leptin and adiponectin production, adipocyte diameter and aromatase level) and progenotoxic factors which characterize DNA damage (8-OHdG) and such cancer promoters as tumor necrosis (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate reactive products (TRP), macrophage/histiocyte infiltration, estrogen 4-hydroxylase expression (CYP1B1) in mammary fat located 1.5-2 cm or not less than 5 cm away from tumor edge. Thirty-three pairs of mammary fat samples from 23 menopausal and 10 cycling patients were used. Closer proximity of mammary fat involved intensified biosynthesis of estrogens (as shown by aromatase level) and their conversion to catechol derivatives (as shown by CYP1B1 concentration) as well as accumulation of 8-OH-dG. Smoking and hyperglycemic patients and those with considerable mammary fat volume revealed accumulations of anti-inflammatory and progenotoxic cytokines (IL-6 or TNF-alpha). Hence, hormonal/progenotoxic ratio in mammary fat can be identified both by topographic, systemic and environmental factors.

Since breast cancer may emerge both before and after menopause onset, relevant forms of the disease show marked biological and clinical differences. Intrinsic properties of mammary fat located in the vicinity of tumor, which play a definitive role in stromal-epithelial interactions, are an important factor of development of such differences. The DNA damage promoting hormonal (leptin and adiponectin production, aromatase activity) and progenotoxic. The properties of mammary fat such as formation of tumor necrosis factor, interleukin-6, nitric oxide, malonic aldehyde, macrophage/histiocyte infiltration and estrogen 4-hydroxylase expression, were studied in mammary fat tissue of 95 patients with receptor-positive or receptor-negative breast tumors (reproductive--25, menopausal--70). It was found that progenotoxic properties might somewhat predominate, as far as differences in parameters and pathways are concerned, both in menopausal and still cycling patients. Hence, progenotoxic damage which represents mammary fat tissue status is perhaps modified by a number of genetic and mitochondrial factors. It may exert unfavorable effect on the course of the disease within a fairly wide period.

About 30-40% of breast cancers lack steroid receptors (ER and/or PR) at diagnosis that worsen prognosis and limit the usage of hormone therapy. The aim of this paper has been to study the role of DNA-damaging factors as the potential modifiers of the receptor-negative tumors incidence.The investigation consisted of two principal parts. In one of them ER and PR content was measured in breast cancer samples from 2284 primary patients (350 of them - current or previous smokers). In separately studied subgroup of 1010 patients 95 suffered with diabetes mellitus type II.As it was shown, smokers and diabetics carry more frequently (p = or0.05) tumors with phenotypes ER+PR- and PR- only in the group of women with conserved menstrual cycle that is in case of relatively higher estrogenic stimulation. In another part of the investigation immunohistochemical study of DNA damage marker - 8-hydroxy-2-deoxyguanosine (8-OH-dG) in 16 R(-) and 18 R(+) breast cancer specimens demonstrated more frequent positive staining in the former group of samples (p = 0.05). Besides, as it was revealed in breast cancer cell line MCF-7 the combination of estradiol with aryl hydrocarbonic receptors agonist beta-naphtoflavone induced pronounced genotoxic damage (by 8-OH-dG content) in association with the loss of ER.Thus, pro-genotoxic status (smoking, diabetes) and direct signs of genotoxic injury, in accordance with regularities of the phenomenon of switching of estrogen effects can be reckoned among the factors promoting the development of receptor-negative breast cancer.

The clinical and endocrine-related effects of 2-week preoperative treatment of endometrial carcinoma patients with a non-steroid inhibitor of letrozole aromatase (femara 2.5 mg/day, n=10) and a steroid inactivator of the enzyme (exemestane 25 mg/day, n=13) were compared. In the first group, pain relief in the lower part of the belly and/or decreased uterine discharge were reported in two cases, as well as a 31% drop in the mean endometrial M-echo (ultrasound) signal. In the exemestane group, two patients revealed moderate uterine discharge decrease matched by a 15.6% decrease in M-signal intensity; no tumor was detected in another patient on completion of the course. Letrozole effect was relatively greater when such parameters as tumor-tissue aromatase level, estrogen concentration in vaginal smear and blood-cholesterol, FSH and LH levels were taken into consideration. However, exemestane therapy involved a relatively sharper drop in the levels of tumor receptors of progesterone and a significantly higher estrogen/progesterone receptor ratio. Hence, no matter how short treatment duration was, both steroid and non-steroid aromatase inhibitors induced effects predominantly associated with lowering estrogen production in endometrial carcinoma patients. This makes a case for further clinical trials of these drugs to deal with the pathology.

Cognitive dysfunction may be associated with the presence of an array of hormono-metabolic factors of risk for certain basic noninfectious diseases, supposedly, including cancer. The investigation was concerned with an appraisal of such cognitive functions as verbal and eye memory and ability to concentrate in endometrial and colorectal cancer patients versus hormonometabolic status and relevant parameters in menopausal women. The indices of short-term memory and concentration in endometrial carcinoma were significantly higher than both in colorectal cancer and osteoporotic patients. However, they were not among healthy women of the same age. A whole range of relationships between said indices and glucose- and estradiol levels in blood serum of patients was studied. No link was established between blood-serum cholesterol, b-lipoproteide and insulin concentration in patients, on the one hand, and cognitive function, on the other. Further research is expected to disclose the ties of the latter with other hormono-metabolic factors as well as tumor-related stress.

Examinations of patients with breast cancer and mammary fibroadenomatosis suggest a relationship between the secretion of interleukin-1β and tumor necrosis factor by blood mononuclears, on the one hand, and patients' age, body weight, and body fat, on the other. A modifying (discoordinating) role of tobacco smoking in the realization of this process is noted.

Data are summarized on experimental means of induction of PSEE and its modification/prevention with the aim to achieve optimal ratio of estrogenic effects (as low as possible genotoxicity in combination with satisfactory and excessive hormonal action). Among studied agents were ethanol, tobacco smoke, irradiation, aging (as PSEE inductors) and carnosine, N-acetylcystein, vit. E and C, melatonin, swimming and antiestrogen ICI 182780 (as PSEE modificators).

We studied the influence of various methods for correction of age-related changes (administration of N-acetyl-L-cysteine, vitamins C and E, melatonin, and carnosine and swimming training) on the realization of estrogens effects in ovariectomized rats. The proliferation index in the endometrium decreased in 12-14-month-old control animals. The weight of the uterus, percentage of "comets", and average length of their tail in estradiol-treated rats far surpassed the corresponding parameters in control animals. Administration of melatonin and N-acetyl-L-cysteine and swimming training corrected these genotoxic abnormalities. Our results indicate that aging induces incomplete variant of the phenomenon for switching of estrogen's effects (increase in the severity of genotoxic damage without facilitation of the hormonal effect). These methods for correction of age-related changes have not only common, but also distinguishing characteristics compared to correction of changed induced by drinking of ethanol in various concentrations, whole body gamma-irradiation, and exposure to tobacco smoke.

Female rats (aged three months at the start of the study) were kept for four months on drinking water (group 1) or 5% ethanol. Rats drinking ethanol were additionally divided into six groups (groups 2-7). During the next two months of the experiment, animals of group 2 continued to drink only ethanol, while rats of group 3 additionally received N-acetylcysteine, those of group 4 received ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E), those of group 5 received melatonin, those of group 6 received carnosine, and those of group 7 swam in the so-called training regime for five days a week. All animals underwent bilateral ovariectomy 2.5 weeks before experiments ended, and were given daily i.m. estradiol (2 microg) during the 11 days before the last experimental day. After treatments, blood estradiol and cholesterol levels were measured, along with progesterone receptor levels, peroxidase activity, the index of proliferation, the proportions of cells in the S and G2/M phases, the thickness of the endometrium, and the extent of DNA damage (using the "comet" technique) in uterine tissue. Liver estradiol 2-hydroxylase activity was also measured. The results led to the conclusion that drinking of 5% ethanol in combination with administration of estrogens was accompanied by induction of genotoxic (G) changes in the uterus and that this was prevented by administration of N-acetylcysteine and melatonin. The combination of vitamins C and E increased some of the manifestations of the hormonal (H) effect of estrogens (uterine weight and induction of progesterone receptors), but weakened others (the index of proliferation). As a result, the combination of N-acetylcysteine and optimum doses of ascorbic acid and alpha-tocopherol can be recommended for preventing the estrogen effect-switching phenomenon (increases in the G component on the background of weakening of the H component), which is seen particularly in patients consuming excessive amounts of alcohol, increasing the risk that the genotoxic version of hormonal cancerogenesis will develop.

Drinking of 5% ethanol in combination with estradiol induced genotoxic (G) changes in the rat uterine tissue. The changes could be prevented by N-acetylcysteine or melatonin. The data obtained suggest that ascorbic acid and alpha-tocopherol may be recommended in combination with N-acetylcysteine for repair of estrogen effect switching phenomenon.

The effect of gamma-irradiation on the realization of the effects of estrogens was studied on rats treated with N-acetylcysteine, vitamins C and E, melatonin, and carnosine or subjected to forced swimming in a training mode. Irradiation (0.2 Gy) in combination with estrogens and without correction therapy induced genotoxic changes in the uterus, while irradiation in a higher dose (2 Gy) predominantly potentiated the hormonal effect of estrogens. Correction of the revealed abnormalities was achieved mainly with carnosine. The peculiarities of "estrogen toggle (re-targeting) effect" under the effect of gamma-irradiation and its elimination differed from those induced by ethanol intake or tobacco smoking, which is important for understanding the mechanisms of hormone-induced carcinogenesis.

A strong connection is known to exist between initiation/promotion of endometrial cancer and excess of estrogens. Therefore, participation of certain alleles of genetic polymorphisms in steroid biosynthesis or metabolism may be responsible for predisposition to the disease. The present study, comparing CYP19 (aromatase) gene polymorphism in 85 patients and 110 healthy females, pointed to a more frequent occurrence of relatively longer alleles (A6 and A7) of the CYP19 gene in the former group. Furthermore, precisely those genotypes co-occurred more frequently with elevated blood levels of estradiol and testosterone in postmenopausal patients. Hence, CYP19 gene polymorphism may be regarded as a factor of genetic risk for endometrial carcinoma.

Extragonadal aromatization plays an important role in many physiological and pathological conditions. It has been found that incubation of the peripheral blood mononuclears in the RPMI-1640 medium with 10% fetal calf serum during 48 hrs is able to induce the aromatase gene expression. The latter did not occur in 11 samples of mononuclears of the intra-tissue leukocyte infiltration which finding needs further investigation. The data obtained suggest that the possibility of the aromatase gene induction in leukocytes is associated with the cellular fraction capable of the substrate adhesion.

Body weight, body mass index, body fat, lean body mass, blood-glucose, cholesterol, HDL-cholesterol, triglyceride, beta-lipoproteins, insulin, gonadotropin, estradiol, testosterone, SHBG, T3, T4 and TSH levels as well as estradiol and progesterone receptor levels in excised tumor were studied in 40 patients with breast cancer prior to conservative treatment. Said anthropometric, metabolic and hormonal parameters were compared with the index of lymphocytic infiltration of tumor selected as a prognostic factor. A significant correlation between high lymphocytic infiltration (2.5 points), low body mass and fat was identified. Also, smoking contributed to loss of body mass and fat; however, it caused lymphocytic infiltration to rise. Moderate body mass, relatively low fat level and positive receptor status are among factors of good prognosis in breast cancer of early stages.

Blood lymphocytes from 26 women were cultivated in RPMI-1640 for 72 hrs with or without dexamethasone, dbcAMP, and TPA. Androstenedione conversion was most often activated by the dbcAMP, then by Dex and TPA. Response to dbcAMP was most obvious in women under 50, whereas response to Dex--in women over 50. Aromatase inhibitor fadrosol displayed a tendency towards prevention of the activation of androstenedione conversion in cultivated lymphocytes. A possibility of aromatase gene induction in cultivated lymphocytes cannot be completely excluded and demands further investigation with the aid of molecular-genetic methods.

Lymphocytes were isolated from 43 surgical samples of breast cancer after tumor enzyme digestion and Ficoll/Verographine procedure. In all, 23 specimens from lymphocytic-tissue infiltrates were analyzed (in some cases, material from 2 or 3 patients was combined). The ability of tumor-infiltrating lymphocytes (TIL) to convert androstenedione was demonstrated, as evaluated by hard-water release from the androgenic precursor 3H-1beta-androstenedione. In material obtained from menopausal women this ability was higher than in the women of reproductive age. A positive correlation was revealed between the level of androstenedione conversion in TIL and aromatase activity in tumor tissue, while no correlation was shown between androstenedione conversion in TIL and percentage of tumor cells in lymphocytic suspension. The data obtained suggest that factors secreted by a neoplasm are able to induce aromatase gene expression in TIL.

Lymphocyte infiltration of tumor was studied vis-a-vis hormone metabolic status, tumor tissue hormone sensitivity and tobacco smoking, in 113 breast cancer patients, aged 25-77. On the average, no correlation was established between degree of lymphocyte infiltration in breast tumor and age and menopause onset. In smoking menopausal patients, lymphocyte infiltration was found to be higher than in non-smokers (p0.05). There was a direct correlation between the rate of lymphocyte infiltration and the level of progesterone receptors in tumor. Some subgroups displayed a direct correlation between infiltration and sex-binding globulin, cholesterol, luteinizing hormone in blood, and lean body mass. It was matched by an inverse correlation between lymphocyte infiltration and blood-thyroid hormone concentration, urine catecholamines and free cortisol excretion and fat/lean body mass ratio. Considering the abovesaid as well as the lymphocyte ability to perform the dual function of immunocytes and hormonocytes, it is suggested that the results may be used in both the study of lymphocyte infiltration and research in means of its control.

The authors have assessed the effects of 7 metabolic and 5 neutral drugs and their combinations on the basal blood concentration of the growth hormone (GH) and on the sensitivity of GH-regulating centers to homeostatic glucose inhibition. No significant changes in GH basal level were revealed. Nacom and a combination of vitamins E and C reduced the threshold sensitivity to glucose inhibition of the GH, whereas miscleron and trental elevated this threshold sensitivity. A combination of butamid and nacom had the highest stimulatory effect on the cellular immunity and macrophagal function, that may be mediated by enhanced GH secretion. In subjects with the 'superior' (android) type of obesity GH basal concentration and its sensitivity to glucose inhibition were lower than in those with the 'inferior' (gynoid) type, this being true after the drug discontinuation.

Cytospectrophotometric analysis showed that the ratio between activities of aerobic H forms of lactate dehydrogenase (LD) and the activity of its anaerobic M forms in cerebral cortical neurons and cerebellar Purkinje cells and also in their glial satellite cells of rats of the Krushinskii-Molodkina and Wistar strains is higher than in motoneurons in the anterior horns of the spinal cord and their perineuronal glia. In Krushinskii-Molodkina rats (with genetically determined high sensitivity to audiogenic seizures) epileptiform audiogenic seizures were accompanied by marked activation of both H and M forms of LD in the cortical neurons but by absence of changes in the perineuronal glia. In the spinal motoneurons, on the other hand, the activity of all forms of LD was unchanged, whereas in the neuroglial cells surrounding these neurons activity of the H forms of LD was definitely increased. During the seizures an increase in activity of M forms of LD was found in the cerebellar Purkinje cells but a decrease in their activity in the glial satellite cells.

A correlation was made between the complex of metabolic indices (the concentration of free fatty acids, cholesterol, beta-lipoproteids and triglycerids in blood) and the complex of immunological indices (the number of T-lymphocytes, blastogenic reaction of lymphocytes, lysosomal and phagocytic activity of macrophages) in healthy females of two age groups and in breast cancer patients. There were examined 20 healthy females aged 18-29, 19 healthy females aged 40-78 and 37 primary breast cancer patients, and also 30 patients being in the state of remission after the radical treatment, their age was analogous to that of the second control age group. It was stated that healthy females with age show a parallel worsening of metabolic and immunological indices (the correlation coefficient being equal to -0.57 and -0.56 accordingly (P less than 0.01 and P less than 0.02) that corresponds to the phenomenon of metabolic immunodepression. The same phenomenon is observed in breast cancer patients at the stage of clinical remission (r = 0.42, P = 0.02). Contrary, in primary patients despite analogously decreased immunity the correlation coefficient was -0.23. Consequently, the mechanism of immunosuppressive effect of the tumor seems not to be related to the changed concentration in blood of the indices under study.

The effects of administration of phenformin and clofibrate to 32 breast cancer patients who underwent radical mastectomy and suffered from hormonal metabolic disturbances involving a decline in immunologic response were investigated. It was demonstrated that treatment with these drugs during 2--7 months results in an improvement in metabolic parameters and delayed hypersensitivity reaction to DNCB, tuberculin and candidin (75.5% of cases), an increase in T lymphocyte count (56.3%) and an improvement of the reaction of lymphocyte blast transformation (66.6%). The improvement in the immunologic status of the patients persisted for 6--8 weeks after the stoppage of phenformin administration; a gradual decline in immunologic response and return to the original level were recorded 4--6 months after stoppage and phenformin therapy. The effect of clofibrate on metabolic and immunologic parameters did not manifest itself as soon as 6--8 weeks after stoppage. Elimination of metabolic immunodepression, which gradually develops in the course of normal ageing and tumor process, should be the main objective of metabolic immunotherapy. To this end, therapeutic means, other than phenformin and clofibrate, may be used provided they exert the same effects on carbohydrate-fat metabolism. The desirability of study of the effects of a long-term course of drugs of this kind on the therapy of cancer patients is discussed.

Blood somatomedin activity observed in patients with cancer of the corpus uteri, breast, colon and rectum, pancreas, ovary and lung proved to exceed those in control by 140-300%. The said parameter was found to depend upon endocrine-metabolic changes, relatively higher levels being registered in overweight patients and those with hypertriglyceridemia. Changes of varying degree in somatomedin activity and growth hormone levels produced by insulin and glucose in patients with breast and uterine cancer pointed to hormonal dependence of the parameter. Also, the effect is a circumstantial evidence for negative feedback between growth hormone and somatomedin production. In patients with cancer of the breast, uterus and lung, a significant correlation was established between somatomedin activity, on the one hand, and monocyte. B-lymphocyte and T-active lymphocyte levels, on the other, matched by an inverse one with T-lymphocyte level and blastogenic reaction of lymphocytes.