Acute Administration of Tibolone Prevents Oxidative Stress in Ovariectomized Rats Fed High-Fat-and-Fructose Diet

Abstract

In addition to oxidative stress due to the increase of free radicals, estrogen deficiency is associated with changes in enzymatic activity, glutathione redox ratio (GSH/GSSG), and the content of oxidative markers such as malondialdehyde. Tibolone, a synthetic steroid, has been used as an elective treatment for the relief of menopausal symptoms. However, the acute effects of hormonal therapy with tibolone on metabolic parameters and oxidative stress markers associated with the first stages of estrogen deficiency are still unknown. The study aimed to evaluate if the acute administration of tibolone reduces oxidative stress in ovariectomized rats fed high-fat-and-fructose diet. Rats were fed a standard diet or a diet consisting of 10% lard-supplemented chow and 20% high-fructose syrup in the drinking water plus tibolone or vehicle for seven days. Weight, cholesterol, triglycerides, and glucose levels, as well as antioxidant enzymes and oxidative stress markers were quantified in the serum of each experimental group. It was observed that seven days of diet and tibolone treatment in the ovariectomized group reduced weight, triglycerides, cholesterol, glucose levels and advanced glycation end products but did not change GSH/GSSG ratio nor the enzymatic activity of superoxide dismutase. Also, both glutathione peroxidase and glutathione reductase activity decreased, as well as malondialdehyde levels. These results suggest that the acute treatment with tibolone prevented the changes in the metabolic parameters analyzed as well as the increase in the levels of malondialdehyde and AGEs induced by ovariectomy and high-fat diet.

Key words

hormonal therapy - estrogen deficiency - glutathione - malondialdehyde - advanced glycation end products

• References

• 1 Cóppola F, Nader J, Aguirre R. et al. Metabolismo de los estrógenos endógenos y cáncer de mama. Rev Med Uruguay 2005; 21: 15-22
• 2 Escalante-Gómez C, Quesada-Mora S, Zeledón-Sánchez F. et al. [Oxidative profile of the menopausal woman: Estrogens’ role in the prevention and treatment of diseases]. Acta Med Costarric 2009; 51: 206-211
• 3 Agarwal A, Gupta S, Sekhon L. et al. Redox considerations in female reproductive function and assisted reproduction: from molecular mechanisms to health implications. Antioxid Redox Signal 2008; 10: 1375-1403
• 4 Rivera MDC, Bayona ASY. Climaterio y función sexual: un abordaje integral a la sexualidad femenina. CES Salud Pública 2014; 5: 70-76
• 5 Pacheco J. Estrés oxidativo en el climaterio y menopausia y cáncer ginecológico. Rev Per Ginecol Obstet 2010; 56: 108-119
• 6 Sánchez-Rodríguez MA, Zacarías-Flores M, Arronte-Rosales A. et al. Menopause as risk factor for oxidative stress. Menopause 2012; 19: 361-367
• 7 Denzoin VLA, Soraci AL, Tapia MO. Homeostasis del glutatión. Acta Bioquim Clin Latinoam 2013; 47: 529-539
• 8 Sies H. Oxidative stress: from basic research to clinical application. Am J Med 1991; 91 3C 31S-38S
• 9 Kanaya AM, Herrington D, Vittinghoff E. et al. Heart and Estrogen/progestin Replacement Study. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138: 1-9
• 10 Silva-Vial R. Menopausia y terapia de reemplazo hormonal. Rev Med Clin Las Condes 2003; 14: 1-11
• 11 Biglia N, Maffei S, Lello S. et al. Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials. Gynecol Endocrinol 2010; 26: 804-814
• 12 Farfán-García ED, Castillo-Hernández MC, Pinto-Almazán R. et al. Tibolone prevents oxidation and ameliorates cholinergic deficit induced by ozone exposure in the male rat hippocampus. Neurochem Res 2014; 39: 1776-1786
• 13 Henriques HN, Câmara NR, de Carvalho AC. et al. [Effect of high doses of tibolone in body weight and lipid profile of ovariectomized rats]. Rev Bras Ginecol Obstet 2010; 32: 88-93
• 14 Vassalle C, Cicinelli E, Lello S. et al. Effects of menopause and tibolone on different cardiovascular biomarkers in healthy women. Gynecol Endocrinol 2011; 27: 163-169
• 15 Gallagher JC, Baylink DJ, Freeman R. et al. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose-finding studies. J Clin Endocrinol Metab 2001; 86: 4717-4726
• 16 Waynforth HB, Flecknell PA. Experimental and surgical technique in the rat. London: Academic Press; 1992: 276-278
• 17 Pinto-Almazán R, Rivas-Arancibia S, Farfán-García ED. et al. Efecto neuroprotector de la tibolona contra el estrés oxidativo inducido por la exposición a ozono. Rev Neurol 2014; 58: 441-448
• 18 Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 1976; 71: 952-958
• 19 Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissues with Ellman’s reagent. Anal Biochem 1968; 25: 192-205
• 20 Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 1969; 27: 502-522
• 21 Münch G, Mayer S, Michaelis J. et al. Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta 1997; 1360: 17-29
• 22 Henle T, Deppisch R, Beck W. et al. Advanced glycated end-products (AGE) during haemodialysis treatment: discrepant results with different methodologies reflecting the heterogeneity of AGE compounds. Nephrol Dial Transplant 1999; 14: 1968-1975
• 23 Viña J, Perez C, Furukawa T. et al. Effect of oral glutathione on hepatic glutathione levels in rats and mice. Br J Nutr 1989; 62: 683-691
• 24 Griffith OW. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 1999; 27: 922-935
• 25 Calvo-Ochoa E, Hernández-Ortega K, Ferrera P. et al. Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus. J Cereb Blood Flow Metab 2014; 34: 1001-1008
• 26 Chen Y, Heiman ML. Increased weight gain after ovariectomy is not a consequence of leptin resistance. Am J Physiol Endocrinol Metab 2001; 280: E315-E322
• 27 Kim KW, Sohn JW, Kohno D. et al. SF-1 in the ventral medial hypothalamic nucleus: a key regulator of homeostasis. Mol Cell Endocrinol 2011; 336: 219-223
• 28 Hart-Unger S, Korach KS. Estrogens and obesity: Is it all in our heads?. Cell Metab 2011; 14: 435-436
• 29 Pedram A, Razandi M, Blumberg B. et al. Membrane and nuclear estrogen receptor α collaborate to suppress adipogenesis but not triglyceride content. FASEB J 2016; 30: 230-240
• 30 Milewicz A, Tworowska U, Demissie M. Menopausal obesity—myth or fact?. Climacteric 2001; 4: 273-283
• 31 Feigelson HS, Jonas CR, Teras LR. et al. Weight gain, body mass index, hormone replacement therapy, and postmenopausal breast cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev 2004; 13: 220-224
• 32 Demir B, Ozturkoglu E, Solaroglu A. et al. The effects of estrogen therapy and estrogen combined with different androgenic progestins on carbohydrate and lipid metabolism in overweight-obese younger postmenopausal women. Gynecol Endocrinol 2008; 24: 347-353
• 33 Kristensen K, Pedersen SB, Vestergaard P. et al. Hormone replacement therapy affects body composition and leptin differently in obese and non-obese postmenopausal women. J Endocrinol 1999; 163: 55-62
• 34 Beato M, Chávez S, Truss M. Transcriptional regulation by steroid hormones. Steroids 1996; 61: 240-251
• 35 Guyard B, Fricker J, Brigant L. et al. Effects of ovarian steroids on energy balance in rats fed a highly palatable diet. Metabolism 1991; 40: 529-533
• 36 Lizcano F, Guzmán G. Estrogen deficiency and the origin of obesity during menopause. BioMed Res Int 2014; 2014: 757461
• 37 Villanueva LA, Ortega R, Morimoto S. et al. Effects of tibolone on lipid and glucose metabolism as well as insulin secretion in postmenopausal women. Ginecol Obstet Mex 1999; 67: 473-477
• 38 Díaz-Casasola L, Luna-Pichardo D. Advanced glycation end products in cardiovascular disease as a complication of diabetes. Rev Med Inv 2016; 4: 52-57
• 39 Aragno M, Mastrocola R. Dietary sugars and endogenous formation of advanced glycation endproducts: emerging mechanisms of disease. Nutrients 2017; 9: E385
• 40 Cagnacci A, Soldani R, Carriero PL. et al. Effects of low doses of transdermal 17β-estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metabol 1992; 74: 1396-1400
• 41 Guerra RC, Zuñiga-Muñoz A, Guarner Lans V. et al. Modulation of the activities of catalase, Cu-Zn, Mn superoxide dismutase, and glutathione peroxidase in adipocyte from ovariectomised female rats with metabolic syndrome. Int J Endocrinol 2014; 2014: 175080
• 42 Ye ZW, Zhang J, Townsend DM. et al. Oxidative stress, redox regulation and diseases of cellular differentiation. Biochim Biophys Acta 2015; 1850: 1607-1621
• 43 Ji-Young A, Hyeyoon Eo, Yunsook L. Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidative stress in high-fat diet-fed mice. Genes Nutr 2015; 10: 46
• 44 Di Toro C. Glutatión como agente protector endógeno en las enfermedades degenerativas y psiquiátricas. Psicofarmacología 2003; 22: 12-16
• 45 Cisneros R, Oré R, Arnao I. et al. Value of reduced/oxidized glutathione (GSH/GSSG) in diabetic rats treated with maca (Lepidium meyenii Walp). An Fac Med 2011; 72: 107-111
• 46 Bloch-Damti A, Bashan N. Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxid Redox Signal 2005; 7: 1553-1567
• 47 Dilek M, Nazıroğlu M, Baha Oral H. et al. Melatonin modulates hippocampus NMDA receptors, blood and brain oxidative stress levels in ovariectomized rats. J Membr Biol 2010; 233: 135-142
• 48 Patki G, Solanki N, Atrooz F. et al. Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 2013; 1539: 73-86
• 49 Blacker TS, Duchen MR. Investigating mitochondrial redox state using NADH and NADPH autofluorescence. Free Radic Biol Med 2016; 100: 53-65
• 50 Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40: 405-412
• 51 Nielsen F, Mikkelsen BB, Nielsen JB. et al. Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clin Chem 1997; 43: 1209-1214
• 52 Coelho DF, Pereira-Lancha LO, Chaves DS. et al. Effect of high-fat diets on body composition, lipid metabolism and insulin sensitivity, and the role of exercise on these parameters. Braz J Med Biol Res 2011; 44: 966-972
• 53 Wu P, Zhang F, Dai Y. et al. Serum TNF-α, GTH and MDA of high-fat diet-induced obesity and obesity resistant rats. Saudi. Pharm J 2016; 24: 333-336
• 54 Bellanti F, Matteo M, Rollo T. et al. Sex hormones modulate circulating antioxidant enzymes: impact of estrogen therapy. Redox Biol 2013; 1: 340-346
• 55 Yagi K. Female hormones act as natural antioxidants—a survey of our research. Acta Biochim Pol 1997; 44: 701-709
• 56 Ruiz-Larrea MB, Martín C, Martínez R. et al. Antioxidant activities of estrogens against aqueous and lipophilic radicals; differences between phenol and catechol estrogens. Chem Phys Lipids 2000; 105: 179-188
• 57 Stark J, Varbiro S, Sipos M. et al. Antioxidant effect of the active metabolites of tibolone. Gynecol Endocrinol 2015; 31: 31-35
• 58 Vos RM, Krebbers SF, Verhoeven CH. et al. The in vivo human metabolism of tibolone. Drug Metab Dispos 2002; 30: 106-112
• 59 Guerrero AL, Dorado-Martínez C, Rodríguez A. et al. Effects of vitamin E on ozone-induced memory deficits and lipid peroxidation in rats. Neuroreport 1999; 10: 1689-1692