THE EFFECT OF THIRD-GENERATION AROMATASE INHIBITORS ON LIPID METABOLISM IN HAMSTERS UNDER EXPERIMENTAL DIET-INDUCED METABOLIC SYNDROME

Dmytro V. Lytkin
Ph.D, Sc. D. (Biol.), Prof. Andriy L. Zagayko

Ukraine, Kharkiv, National University of Pharmacy

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Abstract.

Metabolic syndrome is the common disease that mostly manifests in insulin resistance and dyslipidemia. Sex hormones imbalance caused by increased peripheral aromatase activity is also plays an important role in aggressive clinical behavior of metabolic syndrome with dyslipidemia. We evaluated the influence of third-generation aromatase inhibitors on blood lipids in hamsters of different age and sex with diet-induced metabolic syndrome. Preparations daily dose for hamsters were calculated by the animal equivalent doses coefficient from human therapeutic doses, and the treatment period was 21 days. Treated hamsters with metabolic syndrome had significantly lower serum levels of free fatty acids, triglycerides, total cholesterol and low density lipoproteins cholesterol compared to untreated animals. The most efficiency was indicated in adult male hamsters. Collectively, the results show that aromatase inhibitors had significant moderate effect on dyslipidemia correction in hamsters with diet-induced metabolic syndrome. Although the results of experiment suggest that aromatase inhibitors may be studied in clinical trials as medicines for metabolic syndrome therapy.

Keywords: metabolic syndrome, dyslipidemia, aromatase inhibitors, exemestane, letrozole, anastrozole.

References

1. Kolovou GD, Anagnostopoulou KK, Cokkinos DV Pathophysiology of dyslipidemia in the
metabolic syndrome Postgraduate Medical Journal 2005;81:358-366.
2. Jaspinder Kaur, ―A Comprehensive Review on Metabolic Syndrome,‖ Cardiology
Research and Practice, vol. 2014, Article ID 943162, 21 p.
3. Han TS, Lean ME. A clinical perspective of obesity, metabolic syndrome and
cardiovascular disease. JRSM Cardiovascular Disease. 2016;5.
4. Hendrani AD, Adesiyun T, Quispe R, et al. Dyslipidemia management in primary
prevention of cardiovascular disease: Current guidelines and strategies. World Journal of Cardiology. 2016; 8(2):201-210.
5. Diabetic Dyslipidemia Review: An Update on Current Concepts and Management
Guidelines of Diabetic Dyslipidemia Dake, Andrew W. et al. The American Journal of the Medical
Sciences, Volume 351, Issue 4, 361 — 365
6. Ginsberg HN, Huang LS. The insulin resistance syndrome: impact on lipoprotein
metabolism and atherothrombosis. J Cardiovasc Risk 2000;7:325–31.
7. Kolovou GD, Anagnostopoulou KK, Cokkinos DV Pathophysiology of dyslipidemia in the
metabolic syndrome Postgraduate Medical Journal 2005;81:358-366.
8. Ruotolo, G. & Howard, B.V. Dyslipidemia of the metabolic syndrome Curr Cardiol Rep (2002) 4: 494.
9. Testosterone and Sex Hormone–Binding Globulin Predict the Metabolic Syndrome and
Diabetes in Middle-Aged Men David E. Laaksonen, Leo Niskanen, Kari Punnonen, Kristiina
Nyyssönen, Tomi-Pekka Tuomainen, Veli-Pekka Valkonen, Riitta Salonen, Jukka T. Salonen Diabetes Care May 2004, 27 (5) 1036-1041.
10. Phan BAP, Toth PP. Dyslipidemia in women: etiology and management. International
Journal of Women’s Health. 2014;6:185-194.
11. Shen M, Shi H. Sex Hormones and Their Receptors Regulate Liver Energy
Homeostasis. International Journal of Endocrinology. 2015;2015:294278.
12. Gao H., Fält S., Sandelin A., Gustafsson J.-Å., Dahlman-Wright K. Genome-wide
identification of estrogen receptor α-binding sites in mouse liver. Molecular
Endocrinology. 2008;22(1):10–22.
13. Ribas V., Nguyen M. T. A., Henstridge D. C., et al. Impaired oxidative metabolism and
inflammation are associated with insulin resistance in ERalpha-deficient mice. The American Journal of Physiology—Endocrinology and Metabolism. 2010;298(2):304–319.
14. Tiano J. P., Delghingaro-Augusto V., Le May C., et al. Estrogen receptor activation
reduces lipid synthesis in pancreatic islets and prevents beta cell failure in rodent models of type
2 diabetes. The Journal of Clinical Investigation. 2011;121(8):3331–3342.
15. Bulun S. E., Chen D., Moy I. et al. Aromatase, breast cancer and obesity: a complex
interaction. Trends Endocrinol Metab. 2012; №23: 83–89.
16. Zumoff B. Relationship of obesity to blood estrogens. Cancer Res. 1982; 42(8): 3289–3294.
17. Boonchaya-anant P., Laichuthai N., Suwannasrisuk P. et al. Changes in testosterone
levels and sex hormone-binding globulin levels in extremely obese men after bariatric surgery
[Published online]. International Journal of Endocrinology. 2016.
18. Cao J., Chen T.M., Hao W.J. et al. Correlation between sex hormone levels and obesity in
the elderly male. Aging Male. 2012; 15(2): 85–9.
19. Kasim-Karakas S. E., Vriend H., Almario R. et al. Effects of dietary carbohydrates on
glucose and lipid metabolism in golden Syrian hamsters. J Lab Clin Med. 1996; 128(2): P. 208-13.
20. Wong S. K., Chin K.-Y., Suhaimi F. Hj. Animal models of metabolic syndrome: a
review. Nutr Metab (Lond). 2016; 13: 65.
21. Anroop B.N., Shery J. A simple practice guide for dose conversion between animals and
human. J Basic Clin Pharm. 2016; 7(2): 27–31.
22. Lumachi F., Brunello A., Maruzzo M. Treatment of Estrogen Receptor-Positive Breast
Cancer. Current Medicinal Chemistry Volume 20, Issue 5, 2013.
23. Markopoulos, C., Polychronis, A., Zobolas, V. et al. Breast Cancer Res Treat (2005) 93: 61.
24. Nabholtz J-MA. Long-term safety of aromatase inhibitors in the treatment of breast
cancer. Therapeutics and Clinical Risk Management. 2008;4(1):189-204.
25. Bundred NJ. The effects of aromatase inhibitors on lipids and thrombosis. British Journal
of Cancer. 2005;93 (Suppl 1): 23-27.
26. Zidan J, Chetver L, Hussein O, Zucker M. Effect of Letrozole on Plasma Lipids,
Triglycerides, and Estradiol in Postmenopausal Women with Metastatic Breast Cancer. The
Oncologist. 2010;15(11):1159-1163.
27. Gorodeski GI. Update on cardiovascular disease in post-menopausal women. Best Pract
Res Clin Obstet Gynaecol. 2002;16:329–55.
28. Van Londen GJ, Perera S, Vujevich K, et al. The impact of an aromatase inhibitor on
body composition and gonadal hormone levels in women with breast cancer. Breast cancer research and treatment. 2011;125(2):441-446.
29. Ong JM, Kern PA. Effect of feeding and obesity on lipoprotein lipase activity,
immunoreactive protein, and messenger RNA levels in human adipose tissue. Journal of Clinical
Investigation. 1989;84(1):305-311.
30. Comitato R, Saba A, Turrini A, Arganini C, Virgili F. Sex Hormones and Macronutrient
Metabolism. Critical Reviews in Food Science and Nutrition. 2015;55(2):227-241.
doi:10.1080/10408398.2011.651177.
31. Björntorp P1. Hormonal control of regional fat distribution. Hum Reprod. 1997 Oct;12
Suppl 1:21-5.