The effect of estradiol and selective estrogen receptor modulators on lipid profile in the ovariectomized rat model

Hossein Babaahmadi-Rezaei, Saleh Aiiashi, Alireza Kheirollah, Hamid Yaghooti

Abstract


Background and purpose: Menopause can increase the risk of cardiovascular diseases, diabetes mellitus, and metabolic syndrome, principally due to estrogen deficiency. In the current experiment, protective effects of selective estrogen receptor modulators (SERMs) and estradiol (E2), alone and combined, were evaluated in a rat model of menopause.

Experimental approach: Forty-eight female Wistar rats underwent ovariectomy to induce a menopause model. Then, the animals were subjected to receive SERMs including tamoxifen (TAM), raloxifene (RAL), and bazedoxifene (BZA) and E2. Finally, serum and liver tissue samples were collected post-treatment for experimental analysis.

Findings/Results: The induction of menopause by ovariectomy reduced the body weight of animals and altered their food intake. TAM, RAL, ethinyl E2 (EE2), and BZA/conjugated estrogens (BZA/CE) improved the ovariectomy-induced elevation of total cholesterol and low-density lipoprotein (LDL) cholesterol significantly. In this regard, the lowering effects of SERMs were significantly greater than EE2. The increased levels of triglycerides were also alleviated by RAL, EE2, and BZA/CE but not TAM. Moreover, the combination of SERMs, especially BZA/CE therapy, had significantly increasing effects on high-density lipoprotein (HDL) cholesterol levels, in a more effective manner than E2 therapy alone. Low-density lipoprotein receptor gene and protein expression levels were also significantly increased by SERMs. The HDL2 subfraction was found to be significantly enhanced in TAM, RAL, and BZA/CE therapy.

Conclusion and implications: The therapy with SERMs, alone or in combination with E2, may be efficiently utilized instead of E2 replacement therapy in post-menopausal conditions.

 

 


Keywords


Cardiovascular diseases; Estradiol; Estrogen replacement therapy; Lipids; Menopause.

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References


Roberts H, Hickey M. Managing the menopause: an update. Maturitas. 2016;86:53-58.DOI: 10.1016/j.maturitas.2016.01.007.

Dalal PK, Agarwal M. Postmenopausal syndrome. Indian J Psychiatry. 2015;57(Suppl 2):S222-S232.DOI: 10.4103/0019-5545.161483.

Monteiro R, Teixeira D, Calhau C. Estrogen signaling in metabolic inflammation. Mediators Inflamm. 2014;2014:615917,1-20.DOI: 10.1155/2014/615917.

Boldarine VT, Pedroso AP, Neto NIP, Dornellas APS, Nascimento CMO, Oyama LM, et al. High-fat diet intake induces depressive-like behavior in ovariectomized rats. Sci Rep. 2019;9(1):10551,1-9.DOI: 10.1038/s41598-019-47152-1.

Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med (Maywood). 2004;229(11):1127-1135.DOI: 10.1177/153537020422901107.

Kannel WB. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am Heart J. 1987;114(2):413-419.DOI: 10.1016/0002-8703(87)90511-4.

Warjukar P, Jha RK, Kute P. Study of lipid profile, estradiol for evaluation of cardiovascular risk in pre-and post-menopausal women. Int J Curr Res Rev. 2020; 12:71-75.DOI: 10.31782/IJCRR.2020.12179.

Moscucci O, Clarke A. Prophylactic oophorectomy: a historical perspective. J Epidemiol Community Health. 2007;61(3):182-184.DOI: 10.1136/jech.2006.046474.

Salpeter SR, Walsh JME, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab. 2006;8(5):538-554.DOI: 10.1111/j.1463-1326.2005.00545.x.

Kim JK, Levin ER. Estrogen signaling in the cardiovascular system. Nucl Recept Signal. 2006;4:e013,1-5.DOI: 10.1621/nrs.04013.

Fait T. Menopause hormone therapy: latest developments and clinical practice. Drugs Context. 2019;8:212551,1-9.DOI: 10.7573/dic.212551.

Mohammadi-Farani A, Haghighi A, Ghazvineh M. Effects of long term administration of testosterone and estradiol on spatial memory in rats. Res Pharm Sci. 2015;10(5):407-418. PMID: 26752989.

de Lignieres B. Hormone replacement therapy: clinical benefits and side-effects. Maturitas. 1996;23 Suppl:S31-S36.DOI: 10.1016/s0378-5122(96)90012-2.

Maximov PY, Lee TM, Jordan VC. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol. 2013;8(2):135-155.DOI: 10.2174/1574884711308020006.

Khaksari M, Raji-Amirhasani A, Bashiri H, Ebrahimi MN, Azizian H. Protective effects of combining SERMs with estrogen on metabolic parameters in postmenopausal diabetic cardiovascular dysfunction: the role of cytokines and angiotensin II. Steroids. 2022;183:109023,1-9.DOI: 10.1016/j.steroids.2022.109023.

Cano A, Hermenegildo C, Oviedo P, Tarín JJ. Selective estrogen receptor modulators and risk for coronary heart disease. Climacteric. 2007;10(2):97-111.DOI: 10.1080/13697130701258804.

Christodoulakos GE, Lambrinoudaki IV, Botsis DC. The cardiovascular effects of selective estrogen receptor modulators. Ann N Y Acad Sci. 2006;1092:374-384.DOI: 10.1196/annals. 1365.034.

Ke HZ, Chen HK, Simmons HA, Qi H, Crawford DT, Pirie CM, et al. Comparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model. Bone. 1997;20(1):31-39.DOI: 10.1016/s8756-3282(96)00313-4.

Zuckerman SH, Bryan N. Inhibition of LDL oxidation and myeloperoxidase dependent tyrosyl radical formation by the selective estrogen receptor modulator raloxifene (LY139481 HCL). Atherosclerosis. 1996;126(1):65-75.DOI: 10.1016/0021-9150(96)05894-7.

Blumenthal RS, Baranowski B, Dowsett SA. Cardiovascular effects of raloxifene: the arterial and venous systems. Am Heart J. 2004;147(5):783-789.DOI: 10.1016/j.ahj.2003.12.019.

Williams JK, Wagner JD, Li Z, Golden DL, Adams MR. Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys. Arterioscler Thromb Vasc Biol. 1997;17(2): 403-408.DOI: 10.1161/01.atv.17.2.403.

Holm P, Shalmi M, Korsgaard N, Guldhammer B, Skouby SO, Stender S. A partial estrogen receptor agonist with strong antiatherogenic properties without noticeable effect on reproductive tissue in cholesterol-fed female and male rabbits. Arterioscler Thromb Vasc Biol. 1997;17(10):2264-2272.DOI: 10.1161/01.atv.17.10.2264.

Dubner AM, Lu S, Jolly AJ, Noble T, Hinthorn T, Nemenoff RA, et al. Confounding effects of tamoxifen: cautionary and practical considerations for the use of tamoxifen-inducible mouse models in atherosclerosis research-brief report. Arterioscler Thromb Vasc Biol. 2023;43(11):2223-2230.DOI: 10.1161/atvbaha.123.319922.

Gur M, Aslan M, Yildiz A, Demirbag R, Yilmaz R, Selek S, et al. Paraoxonase and arylesterase activities in coronary artery disease. Eur J Clin Invest. 2006;36(11):779-787.DOI: 10.1111/j.1365-2362.2006.01727.x.

Rozenberg O, Rosenblat M, Coleman R, Shih DM, Aviram M. Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice. Free Radic Biol Med. 2003;34(6):774-784.DOI: 10.1016/s0891-5849(02)01429-6.

Butorac D, Celap I, Kačkov S, Robić V, Miletić T, Meštrić ZF, et al. Paraoxonase 1 activity and phenotype distribution in premenopausal and postmenopausal women. Biochem Med (Zagreb). 2014;24(2):273-280.DOI: 10.11613/bm.2014.030.

Lampert C, Arcego DM, Laureano DP, Diehl LA, da Costa Lima IF, Krolow R, et al. Effect of chronic administration of tamoxifen and/or estradiol on feeding behavior, palatable food and metabolic parameters in ovariectomized rats. Physiol Behav. 2013;119:17-24.DOI: 10.1016/j.physbeh.2013.05.026.

Park SB, Lee YJ, Chung CK. Bone mineral density changes after ovariectomy in rats as an osteopenic model: stepwise description of double dorso-lateral approach. J Korean Neurosurg Soc. 2010; 48(4):309-312.DOI: 10.3340/jkns.2010.48.4.309.

Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, et al. Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest. 1994;93(1):63-69.DOI: 10.1172/jci116985.

Lamas AZ, Caliman IF, Dalpiaz PLM, de Melo Jr AF, Abreu GR, Lemos EM, et al. Comparative effects of estrogen, raloxifene and tamoxifen on endothelial dysfunction, inflammatory markers and oxidative stress in ovariectomized rats. Life Sci. 2015; 124:101-109.DOI: 10.1016/j.lfs.2015.01.004.

Meli R, Pacilio M, Raso GM, Esposito E, Coppola A, Nasti A, et al. Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats. Endocrinology. 2004;145(7):3115-3121.DOI: 10.1210/en.2004-0129.

Kharode Y, Bodine PVN, Miller CP, Lyttle CR, Komm BS. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology. 2008;149(12):6084-6091.DOI: 10.1210/en.2008-0817.

Azizian H, Khaksari M, Asadikaram G, Sepehri G, Najafipour H. Therapeutic effects of tamoxifen on metabolic parameters and cytokines modulation in rat model of postmenopausal diabetic cardiovascular dysfunction: role of classic estrogen receptors. Int Immunopharmacol. 2018;65:190-198.DOI: 10.1016/j.intimp.2018.10.009.

Assis RP, Arcaro CA, Gutierres VO, Oliveira JO, Costa PI, Baviera AM, et al. Combined effects of curcumin and lycopene or bixin in yoghurt on inhibition of LDL oxidation and increases in HDL and paraoxonase levels in streptozotocin-diabetic rats. Int J Mol Sci. 2017;18(4):332,1-20.DOI: 10.3390/ijms18040332.

Abbasi Oshaghi E, Khodadadi I, Saidijam M, Yadegarazari R, Shabab N, Tavilani H, et al. Lipid lowering effects of hydroalcoholic extract of Anethum graveolens L. and dill tablet in high cholesterol fed hamsters. Cholesterol. 2015;2015:958560,1-7.DOI: 10.1155/2015/958560.

Vigneswaran K, Hamoda H. Hormone replacement therapy- current recommendations. Best Pract Res Clin Obstet Gynaecol. 2022;81:8-21.DOI: 10.1016/j.bpobgyn.2021.12.001.

Suárez Y, Fernández C, Gómez-Coronado D, Ferruelo AJ, Dávalos A, Martínez-Botas J, et al. Synergistic upregulation of low-density lipoprotein receptor activity by tamoxifen and lovastatin. Cardiovasc Res. 2004;64(2):346-355.DOI: 10.1016/j.cardiores.2004.06.024.

Hozumi Y, Kawano M, Hakamata Y, Miyata M, Jordan VC. Tamoxifen inhibits lipoprotein activity: in vivo and in vitro studies. Horm Res. 2000; 53(1):36-39.DOI: 10.1159/000023511.

Naves-Díaz M, Carrillo-López N, Rodríguez-Rodríguez A, Braga S, Fernández-Coto T, López-Novoa JM, et al. Differential effects of 17beta-estradiol and raloxifene on bone and lipid metabolism in rats with chronic kidney disease and estrogen insufficiency. Menopause. 2010;17(4):766-771.DOI: 10.1097/gme.0b013e3181ce6874.

Dogiparthi A, Aggarwal N, Suri V, Srinivasan R, Malhotra S. Comparative evaluation of raloxifene versus estrogen: progestin on symptomatology, endometrium, and lipid profile in postmenopausal women. J Midlife Health. 2010;1(1):14-18.DOI: 10.4103/0976-7800.66988.

Xu Y, Lin J, Wang S, Xiong J, Zhu Q. Combined estrogen replacement therapy on metabolic control in postmenopausal women with diabetes mellitus. Kaohsiung J Med Sci. 2014;30(7):350-361.DOI: 10.1016/j.kjms.2014.03.002.

Komm BS, Vlasseros F, Samadfam R, Chouinard L, Smith SY. Skeletal effects of bazedoxifene paired with conjugated estrogens in ovariectomized rats. Bone. 2011;49(3):376-386.DOI: 10.1016/j.bone.2011.05.024.

Xu B, Lovre D, Mauvais-Jarvis F. The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: basic and clinical insights. J Diabetes Complications. 2017;31(4):773-779.DOI: 10.1016/j.jdiacomp.2016.12.010.

Hozumi Y, Kawano M, Miyata M. Severe hypertriglyceridemia caused by tamoxifen treatment after breast cancer surgery. Endocr J. 1997;44(5):745-749.DOI: 10.1507/endocrj.44.745.

Hozumi Y, Kawano M, Saito T, Miyata M. Effect of tamoxifen on serum lipid metabolism. J Clin Endocrinol Metab. 1998;83(5):1633-1635.DOI: 10.1210/jcem.83.5.4753.

Persson L, Gälman C, Angelin B, Rudling M. Importance of proprotein convertase subtilisin/kexin type 9 in the hormonal and dietary regulation of rat liver low-density lipoprotein receptors. Endocrinology. 2009;150(3):1140-1146.DOI: 10.1210/en.2008-1281.

Cerrato F, Fernández-Suárez ME, Alonso R, Alonso M, Vázquez C, Pastor O, et al. Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes. Br J Pharmacol. 2015;172(5): 1379-1394.DOI: 10.1111/bph.13016.

Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC. Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Biol. 2001;8(6):499-504.DOI: 10.1038/88556.

Colvin Jr PL. Estrogen increases low-density lipoprotein receptor-independent catabolism of apolipoprotein B in hyperlipidemic rabbits. Metabolism. 1996;45(7):889-896.DOI: 10.1016/s0026-0495(96)90165-1.

Jia YJ, Xu RX, Sun J, Tang Y, Li JJ. Enhanced circulating PCSK9 concentration by berberine through SREBP-2 pathway in high-fat diet-fed rats. J Transl Med. 2014;12:103,1-8.DOI: 10.1186/1479-5876-12-103.

Xu B, Lovre D, Mauvais-Jarvis F. Effect of selective estrogen receptor modulators on metabolic homeostasis. Biochimie. 2016;124:92-97.DOI: 10.1016/j.biochi.2015.06.018.

Ahmad S, Scott JE. Estradiol enhances cell-associated paraoxonase 1 (PON1) activity in vitro without altering PON1 expression. Biochem Biophys Res Commun. 2010;397(3):441-446.DOI: 10.1016/j.bbrc.2010.05.120.

Litvinov D, Mahini H, Garelnabi M. Antioxidant and anti-inflammatory role of paraoxonase 1: implication in arteriosclerosis diseases. N Am J Med Sci. 2012;4(11):523-532.DOI: 10.4103/1947-2714.103310.

Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest. 1998;101(8):1581-1590. DOI: 10.1172/JCI1649.

Tian L, Fu M. The relationship between high-density lipoprotein subclass profile and plasma lipid concentrations. Lipids Health Dis. 2010;9:118,1-9.DOI: 10.1186/1476-511x-9-118.

Gräser T, Rössner P, Schubert K, Müller A, Bönisch U, Oettel M. A comparative study of two levonorgestrel-containing hormone replacement therapy regimens of efficacy and tolerability variables. Maturitas. 1997;28(2):169-179.DOI: 10.1016/s0378-5122(97)00069-8.

Pornel B, Chevallier O, Netelenbos JC. Oral 17beta-estradiol (1 mg) continuously combined with dydrogesterone improves the serum lipid profile of postmenopausal women. Menopause. 2002;9(3): 171-178.DOI: 10.1097/00042192-200205000-00005.

Mahrooz A. Pharmacological interactions of paraoxonase 1 (PON1): a HDL-bound antiatherogenic enzyme. Curr Clin Pharmacol. 2016;11(4):259-264.DOI: 10.2174/1574884711666160915153433.

Su X, Zhang G, Cheng Y, Wang B. New insights into the emerging effects of inflammatory response on HDL particles structure and function. Mol Biol Rep. 2021;48(7):5723-5733.DOI: 10.1007/s11033-021-06553-0.

Neugarten J, Acharya A, Lei J, Silbiger S. Selective estrogen receptor modulators suppress mesangial cell collagen synthesis. Am J Physiol Renal Physiol. 2000;279(2):F309-F318.DOI: 10.1152/ajprenal.2000.279.2.F309.

Patel BM, Desai VJ. Beneficial role of tamoxifen in experimentally induced cardiac hypertrophy. Pharmacol Rep. 2014;66(2):264-272.DOI: 10.1016/j.pharep.2014.02.004.

Fontaine C, Abot A, Billon-Galés A, Flouriot G, Bergès H, Grunenwald E, et al. Tamoxifen elicits atheroprotection through estrogen receptor α AF-1 but does not accelerate reendothelialization. Am J Pathol. 2013;183(1):304-312.DOI: 10.1016/j.ajpath.2013.03.010.

Sumino H, Ichikawa S, Kasama S, Takahashi T, Sakamoto H, Koizumi A, et al. Effects of raloxifene on brachial arterial endothelial function, carotid wall thickness, and arterial stiffness in osteoporotic postmenopausal women. Int Heart J. 2010; 51(1):60-67.DOI: 10.1536/ihj.51.60.

Wu X, Glinn MA, Ostrowski NL, Su Y, Ni B, Cole HW, et al. Raloxifene and estradiol benzoate both fully restore hippocampal choline acetyltransferase activity in ovariectomized rats. Brain Res. 1999;847(1):98-104.DOI: 10.1016/s0006-8993(99)02062-4.

Peano BJ, Crabtree JS, Komm BS, Winneker RC, Harris HA. Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland. Endocrinology. 2009;150(4):1897-1903.DOI: 10.1210/en.2008-1210.


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