Lytkin D. The effect of adipose tissue aromatase activity modulators on the course of experimental metabolic syndrome.

The dissertation is devoted to determination of the adipose tissue aromatase activity implication in the pathogenesis of metabolic syndrome and to experimental justification of the use of aromatase inhibitors for its complex therapy. The effects of exemestane, letrozole and anastrozole on metabolism and hormonal background were studied on the model of experimental metabolic syndrome (MS) in hamsters of different age and both sexes. MS was induced by hypercaloric high fat and fructose diet within 6 weeks. Experimental MS led to obesity, insulin resistance, atherogenic dyslipidemia and hyperestrogenemia in all groups of animals. The drugs were administrated intragastrically for 21 days in equivalent doses recalculated from the average therapeutic for humans On the model of experimental MS it was found, that rising of visceral adipose aromatase activity is highly inverse correlated with serum adiponectin levels reduction. On the other hand, aromatase inhibitors can significantly decrease visceral adipose aromatase activity and level up serum adiponectin content with a high level of inverse correlation. Exemestane significantly inhibited aromatase activity by 48.4-75.5 %, letrozole by 45.7-78.3 %, and anastrozole by 54.2-75.3 % depending on the sex and age of animals compared to negative control. At the same time levels of adiponectin in serum were significantly increased by 51.0-135.7 % under the influenced of aromatase inhibitors administration. The main effect of aromatase inhibitors (to decrease estrogen levels) also was confirmed in conditions of MS with hyperestrogenemia. As for testosterone level, medicines significantly enhanced its level in male animals and made almost no effect in female. The complex effect on MS curse can be characterized as sex steroid hormonal disbalance correction. The undescribed side effect of exemestane was revealed to provoke ascites and increase the serum content of hormones with mineralocorticoid activity (such as aldosterone and cortisol) in female animals with experimental MS. Aromatase inhibitors are able to reduce average body weight and increase protein content in visceral fat with high inverse correlation, that evidences about visceral obesity correction. Moreover, drugs directly reduce the mass of visceral adipose fragments (retroperitoneal and mesenteric). In the treatment of MS aromatase inhibitors prevent the development of steatohepatitis, inflammation and fibrosis of visceral adipose tissue. Morphometric studies confirmed the presence of hypertrophy of visceral adipocytes reduction under the influence of aromatase inhibitors by 53.3-68.7 % of the average adipocyte area compared to negative control. According to the results of lipid metabolism investigation, third generation aromatase inhibitors have therapeutic influence under MS. All medicines have antihyperlipidemic activity and reduce serum holesterol content on account of low density lipoproteins cholesterol, that in most cases led to a decrease in atherogenic index and cholesterol fractions ratio. Exemestane also have property to improve triacylglycerol level, while letrozole and anastrozole lower free fatty acids concentration. Both exemestane and letrozole have been able to effectively correct postprandial hyperglycemia in terms of MS and decrease the area under the glycemic curve during oral glucose tolerance test. Besides, all the drugs cause basal glycemia improvement and treat manifestations of insulin resistance (downregulate insulin level, normalize index of insulin resistance). Also aromatase inhibitors reduce serum level of fructosamine. The third generation aromatase inhibitors are able to development eating behavior and prevent of the leptin resistance. Exemestane, letrozole and anastrozole cause to decrease in number of acts of eating and in their duration, also medicines regulate the content of leptin in serum blood. According to the sum results of the study, aromatase inhibitors under long-term application may have significant corrective effects on the course of experimental metabolic syndrome, which is exhibited in obesity reducing, carbohydrate and lipid metabolism improving, hormonal background and eating behavior normalizing.