The effect of third-generation aromatase inhibitors on aromatase avtivity in visceral adipose tissue


Keywords: exemestane; letrozole; anastrozole; adiponectin; metabolic syndrome

Abstract

Pathogenesis and clinical manifestations of metabolic syndrome (and other conditions characterized by the growth of fat mass and decreased adiponectin content) is associated with an imbalance of sex hormones, which develops under the influence of increased aromatase activity in adipose tissue. Drugs of the aromatase inhibitors therapeutic group are able to suppress the course of the aromatase reaction in the central and peripheral organs and tissues. The aim of our study was to establish the relationship between levels of serum adiponectin and adipose tissue aromatase avtivity in Syrian hamsters of different ages and gender with experimental metabolic syndrome and study the effect of aromatase inhibitors on these indicators. Experimental metabolic syndrome in animals was induced by a high-fat and fructose diet. The drugs were administered during the 21-st day in doses of 3.086 (exemestane), 0.309 (letrozole) and 0.126 mg/kg (anastrozole). The aromatase activity of the visceral adipose tissue was determined by the modified kinetic method based on the amount of the reaction product estradiol converted from testosterone. The content of estradiol in adipose tissue homogenate and serum adiponectin levels were measured by the immune enzyme method. The results showed a high inverse correlation between serum adiponectin and adipose tissue aromatase activity in hamsters. Aromatase inhibitors caused a decrease in the adipose tissue aromatase activity and increase in serum adiponectin levels. Letrazol demonstrated the greatest effect, it reduced aromatase activity in adipose tissue by 72–84% and increased serum adiponectin content by 1.6–1.8 times. At the same time, intra-group correlation of the studied parameters was significant. The results show the relationship between adiponectin level and adipose tissue aromatase activity and ability to change these rates by the way of aromatase inhibitors, which may be useful in clinical practice. Third-generation aromatase inhibitors are promising drugs for metabolic syndrome treatment and require further study in clinical trials.

References

Akyol, M., Demir, L., Alacacioglu, A., Ellidokuz, H., Kucukzeybek, Y., Yildiz, Y., Gumus, Z., Bayoglu, V., Yildiz, I., Salman, T., Varol, U., Kucukzey bek, B., Demir, L., Dirican, A., Sutcu, R., & Tarhan, M. O. (2016). The effects of adjuvant endocrine treatment on serum leptin, serum adiponectin and body composition in patients with breast cancer: The Izmir Oncology Group (IZOG) study. Chemotherapy, 61(2), 57–64.


Biegon, A. (2016). In vivo visualization of aromatase in animals and humans. Frontiers in Neuroendocrinology, 40, 42–51.


Blakemore, J., & Naftolin, F. (2016). Aromatase: Contributions to physiology and disease in women and men. Physiology, 31(4), 258–269.


Boonchaya-anant, P., Laichuthai, N., Suwannasrisuk, P., Houngngam, N., Udomsawaengsup, S., & Snabboon, T. (2016). Changes in testosterone le vels and sex hormone-binding globulin levels in extremely obese men after bariatric surgery. International Journal of Endocrinology, 2016, 1416503.


Bulun, S. E., Chen, D., Moy, I., Brooks, D. C., & Zhao, H. (2012). Aromatase, breast cancer and obesity: A complex interaction. Trends in Endocrino logy and Metabolism: TEM, 23(2), 83–89.


Cao, J., Chen, T. M., Hao, W. J., Li, J., Liu, L., Zhu, B. P., & Li, X. Y. (2012). Correlation between sex hormone levels and obesity in the elderly male. The Aging Male, 15(2), 85–89.


Capllonch-Amer, G., Sbert-Roig, M., Galmés-Pascual, B. M., Proenza, A. M., Lladó, I., Gianotti, M., & García-Palmer, F. J. (2014). Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle. The Journal of Endocrinology, 221(3), 391–403.


Chan, H. J., Petrossian, K., & Chen, S. (2016). Structural and functional charac terization of aromatase, estrogen receptor, and their genes in endocrine-responsive and – resistant breast cancer cells. The Journal of Steroid Bio chemistry and Molecular Biology, 161, 73–83.


Comitato, R., Saba, A., Turrini, A., Arganini, C., & Virgili, F. (2015). Sex hor mones and macronutrient metabolism. Critical Reviews in Food Science and Nutrition, 55(2), 227–241.


Dalbøge, L. S., Pedersen, P. J., Hansen, G., Fabricius, K., Hansen, H. B., Jel sing, J., & Vrang, N. (2015). A hamster model of diet-Induced obesity for preclinical evaluation of anti-obesity, anti-diabetic and lipid modulating agents. Public Library of Science One, 10(8), e0135634.


Ding, Y. S., Guo, S. X., Ma, R. L., Li, S. G., Guo, H., Zhang, J. Y., Zhang, M., Liu, J. M., He, J., Yan, Y. Z., Zhang, W. J., & Liu, L. G. (2015). Associati on of metabolic syndrome with the adiponectin to homeostasis model assessment of insulin resistance ratio. Mediators of Inflammation, 2015, 607364.


Dos Santos, E., Dieudonné, M. N., Leneveu, M. C., Sérazin, V., Rincheval, V., Mignotte, B., Chouillard, E., De Mazancourt, P., Giudicelli, Y., & Pecque ry, R. (2010). Effects of 17beta-estradiol on preadipocyte proliferation in human adipose tissue: Involvement of IGF1-R signaling. Hormone and Metabolic Research, 42(7), 514–520.


Gao, H., Fält, S., Sandelin, A., Gustafsson, J.-Å., & Dahlman-Wright, K. (2008). Genome-wide identification of estrogen receptor α-binding sites in mouse liver. Molecular Endocrinology, 22(1), 10–22.


Ghosh, D., Lo, J., & Egbuta, C. (2016). Recent progress in the discovery of next generation inhibitors of aromatase from the structure-function per spective. Journal of Medicinal Chemistry, 59(11), 5131–5148.


Guarner-Lans, V., Rubio-Ruiz, M. E., Pérez-Torres, I., & Baños de MacCar thy, G. (2011). Relation of aging and sex hormones to metabolic syndrome and cardiovascular disease. Experimental Gerontology, 46(7), 517–523.


Ioannides, S. J., Barlow, P. L., Elwood, J. M., & Porter, D. (2014). Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone re ceptor-positive breast cancer: A systematic review. Breast Cancer Research and Treatment, 147(2), 237–248.


Jones, M. E., Schoemaker, M., Rae, M., Folkerd, E. J., Dowsett, M., Ashworth, A., & Swerdlow, A. J. (2013) Changes in estradiol and testosterone levels in postmenopausal women after changes in body mass index. The Journal of Clinical Endocrinology and Metabolism, 98(7), 2967–2974.


Kim, C., & Halter, J. B. (2014). Endogenous sex hormones, metabolic syndro me, and diabetes in men and women. Current Cardiology Reports, 16(4), 467.


Körner, A., Wabitsch, M., Seidel, B., Fischer-Posovszky, P., Berthold, A., Stumvoll, M., Blüher, M., Kratzsch, J., & Kiess, W. (2005). Adiponectin expression in humans is dependent on differentiation of adipocytes and down-regulated by humoral serum components of high molecular weight. Biochemical and Biophysical Research Communications, 337(2), 540–550.


Kunnari, A., Santaniemi, M., Jokela, M., Karjalainen, A. H., Heikkinen, J., Uk kola, O., & Kesäniemi, Y. A. (2008). Estrogen replacement therapy de creases plasma adiponectin but not resistin in postmenopausal women. Metabolism, 57(11), 1509–1515.


Lapauw, B., T'Sjoen, G., Mahmoud, A., Kaufman, J. M., & Ruige, J. B. (2009). Short-term aromatase inhibition: Effects on glucose metabolism and serum leptin levels in young and elderly men. European Journal of Endo crinology, 160(3), 397–402.


Lønning., P. E., Haynes, B. P., & Dowsett, M. (2014). Relationship of body mass index with aromatisation and plasma and tissue oestrogen levels in post menopausal breast cancer patients treated with aromatase inhibitors. Euro pean Journal of Cancer, 50(6), 1055–1064.


Lytkin, D. V., & Zagayko, A. L. (2017). The effect of third-generation aroma tase inhibitors on lipid metabolism in hamsters under experimental diet-induced metabolic syndrome. World Science, 29(2), 23–27.


Mantas, D., Kostakis, J. D., & Markopoulos, C. (2016). Aromatase inhibitors: A comprehensive review in mechanisms of action, side effects and treat ment in postmenopausal early breast cancer patients. Hellenic Journal of Surgery, 88, 245.


Markopoulos, C., Polychronis, A., Zobolas, V., Xepapadakis, G., Papadiaman tis, J., Koukouras, D., Lappas, H., & Gogas, H. (2005). The effect of exe mestane on the lipidemic profile of postmenopausal early breast cancer patients: Preliminary results of the TEAM Greek sub-study. Breast Cancer Research and Treatment, 93(1), 61–66.


Matsushita, Y., Nakagawa, T., Yamamoto, S., Kato, T., Ouchi, T., Kikuchi, N., Takahashi, Y., Yokoyama, T., Mizoue, T., & Noda, M. (2013). Adiponectin and visceral fat associate with cardiovascular risk factors. Obesity (Silver Spring), 22(1), 287–291.


Mauro, L., Pellegrino, M., Giordano, F., Ricchio, E., Rizza, P., De Amicis, F., Catalano, S., Bonofiglio, D., Panno, M. L., & Andò, S. (2015). Estrogen receptor-α drives adiponectin effects on cyclin D1 expression in breast cancer cells. The FASEB Journal, 29(5), 2150–2160.


Mojaddami, A., Sakhteman, A., Fereidoonnezhad, M., Faghih, Z., Najdian, A., Khabnadideh, S., & Rezaei, Z. (2017). Binding mode of triazole derivati ves as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies. Research in Pharmaceutical Sciences, 12(1), 21–30.


Nabholtz, J.-M. A. (2008). Long-term safety of aromatase inhibitors in the treatment of breast cancer. Therapeutics and Clinical Risk Management, 4(1), 189–204.


Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7(2), 27–31.


Nalabolu, M. R., Palasamudram, K., & Jamil, K. (2014). Adiponectin and lep tin molecular actions and clinical significance in breast cancer. Internatio nal Journal of Hematology-Oncology and Stem Cell Research, 8(1), 31–40.


Newbold, R. R., Padilla-Banks, E., & Jefferson, W. N. (2009). Environmental estro gens and obesity. Molecular and Cellular Endocrinology, 304(1–2), 84–89.


Ozkaya, H. M., Comunoglu, N., Keskin, F. E., Oz, B., Haliloglu, O. A., Tanri over, N., Gazioglu, N., & Kadioglu, P. (2016). Locally produced estrogen through aromatization might enhance tissue expression of pituitary tumor transforming gene and fibroblast growth factor 2 in growth hormone-secreting adenomas. Endocrine, 52(3), 632–640.


Pfeiler, G., Königsberg, R., Hadji, P., Fitzal, F., Maroske, M., Dressel-Ban, G., Zellinger, J., Exner, R., Seifert, M., Singer, C., Gnant, M., & Dubsky, P. (2013). Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer. British Journal of Cancer, 109(6), 1522–1527.


Pfeiler, G., Konigsberg, R., Hadji, P., Fitzal, F., Tea, M.-K. M., Vogl, S., Berger, A., Exner, R., Seifert, M., Singer, F. C., Gnant, M., & Dubsky, P. C. (2013). The impact of estrogen depletion by aromatase inhibitors on adiponectin serum levels in postmenopausal patients with breast cancer. Journal of Clinical Oncology, 31(15), in print.


Redmile-Gordon, M. A., Armenise, E., White, R. P., Hirsch, P. R., & Goul ding, K. W. T. (2013). A comparison of two colorimetric assays, based upon Lowry and Bradford techniques, to estimate total protein in soil extracts. Soil Biology and Biochemistry, 67(100), 166–173.


Richards, J. B., Valdes, A. M., Burling K., Perks, U. C., & Spector, T. D. (2007). Serum adiponectin and bone mineral density in women. The Journal of Clinical Endocrinology and Metabolism, 92(4), 1517–1523.


Sun, H., Ehlhardt, W. J., Kulanthaivel, P., Lanza, D. L., Reilly, C. A., & Yost, G. S. (2007). Dehydrogenation of indoline by cytochrome P450 enzymes: A novel “Aromatase” process. Journal of Pharmacology and Experimental Therapeutics, 322(2), 843–851.


Tinwell, H., Rascle, J. B., Colombel, S., Al Khansa, I., Freyberger, A., & Bars, R. (2011). A novel method for measuring aromatase activity in tissue samp les by determining estradiol concentrations. Journal of Applied Toxicolo gy, 31, 446–454.


Tworoger, S. S., Mantzoros, C., & Hankinson, S. E. (2007). Relationship of plasma adiponectin with sex hormone and Insulin-like Growth Factor levels. Obesity, 15, 2217–2224.


Van Londen, G. J., Perera, S., Vujevich, K., Rastogi, P., Lembersky, B., Bruf sky, A., Vogel, V., & Greenspan, S. L. (2011). The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer. Breast Cancer Research and Treatment, 125(2), 441–446.


Viciano, I., & Martí, S. (2016). Theoretical study of the mechanism of exemes tane hydroxylation catalyzed by human aromatase enzyme. The Journal of Physical Chemistry B, 120(13), 3331–3343.


Von Frankenberg, A. D., do Nascimento, F. V., Gatelli, L. E., Nedel, B. L., Garcia, S. P., de Oliveira, C. S., Saddi-Rosa, P., Reis, A. F., Canani, L. H., & Gerchman, F. (2014). Major components of metabolic syndrome and adi ponectin levels: A cross-sectional study. Diabetology and Metabolic Syndrome, 6, 26.


Wong, S. K., Chin, K.-Y., Suhaimi, F. H., Fairus, A., & Ima-Nirwana, S. (2016). Animal models of metabolic syndrome: A review. Nutrition and Metabo lism, 13, 65.


Xu, Q., Wells, C. C., Garman, J. H., Asico, L., Escano, C. S., & Maric, C. (2008). Imbalance in sex hormone levels Exacerbates Diabetic Renal Disease. Hypertension, 51(4), 1218–1224.


Zhao, H., Zhou, L., Shangguan, A. J., & Bulun, S. E. (2016). Aromatase ex pression and regulation in breast and endometrial cancer. Journal of Molecular Endocrinology, 57(1), 19–33.


Zidan, J., Chetver, L., Hussein, O., & Zucker, M. (2010). Effect of letrozole on plasma lipids, triglycerides, and estradiol in postmenopausal women with metastatic breast cancer. The Oncologist, 15(11), 1159–1163.

Published
2018-08-13
How to Cite
Lytkin, D. V., Zagayko, A. L., & Briukhanova, T. O. (2018). The effect of third-generation aromatase inhibitors on aromatase avtivity in visceral adipose tissue. Regulatory Mechanisms in Biosystems, 9(2), 209-215. https://doi.org/https://doi.org/10.15421/021831

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.