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Current Vascular Pharmacology

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ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

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General Review Article

Hypertriglyceridemia: An Infrequent, Difficult-to-predict, Severe Metabolic and Vascular Problem Associated with Estrogen Administration

Author(s): Thomas F. Whayne*

Volume 18, Issue 3, 2020

Page: [254 - 261] Pages: 8

DOI: 10.2174/1570161117666190306102322

Price: $65

Abstract

Supplementary estrogen plays important roles for female patients as convenient birth control, relief of postmenopausal symptoms, and in the management of other selected problems. However, as is the case for essentially all medications, there are side effects. Short of a major pulmonary embolus, the most severe side effect of estrogen would appear to be sporadic, rare, and severe hypertriglyceridemia associated with acute pancreatitis. The occurrence of this fortunately rare problem usually happens in the presence of some preexisting and usually mild increase in triglycerides (TG). A case of chronic and severe recurrent acute pancreatitis is described in the introduction and the management was complete estrogen avoidance. Started close to menopause and continued for a relatively short period, estrogens may have some cardiovascular (CV) benefit but the general recommendation is not to prescribe them for CV disease prevention. Estrogens may contribute to decreased diabetes mellitus (DM) risk and control. Administration of estrogens by the transdermal route may decrease some problems such as venous thromboembolism (VTE) and elevation of TG. Administration of estrogen in the right situation brings significant benefit to the female patient but skillful, careful, and knowledgeable use is essential.

Keywords: Diabetes mellitus, estrogens, hepatic triglyceride lipase, high-density lipoprotein, lipoprotein lipase, low-density lipoprotein, triglycerides.

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[1]
Aztlan-James EA, McLemore M, Taylor D. Multiple unintended pregnancies in U.S. women: a systematic review. Women Health Issues 2017; 27(4): 407-13.
[http://dx.doi.org/10.1016/j.whi.2017.02.002] [PMID: 28284587]
[2]
Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Fertil Steril 2001; 75(5): 898-915.
[http://dx.doi.org/10.1016/S0015-0282(01)01699-5] [PMID: 11334901]
[3]
Aguilar Cordero MJ, Baena García L, Sánchez López AM, et al. Triglyceride levels as a risk factor during pregnancy; biological modeling; systematic review. Nutr Hosp 2015; 32(2): 517-27.
[PMID: 26268079]
[4]
O’Sullivan AJ, Hoffman DM, Ho KK. Estrogen, lipid oxidation, and body fat. N Engl J Med 1995; 333(10): 669-70.
[http://dx.doi.org/10.1056/NEJM199509073331018] [PMID: 7637741]
[5]
Lobo RA, Skinner JB, Lippman JS, Cirillo SJ. Plasma lipids and desogestrel and ethinyl estradiol: a meta-analysis. Fertil Steril 1996; 65(6): 1100-9.
[http://dx.doi.org/10.1016/S0015-0282(16)58321-6] [PMID: 8641480]
[6]
Spellacy WN, Buhi WC, Birk SA, Cabal R. The effects of estrogens, progestogen, oral contraceptives, and intrauterine devices on fasting triglyceride and insulin levels. Fertil Steril 1973; 24(3): 178-84.
[http://dx.doi.org/10.1016/S0015-0282(16)39550-4] [PMID: 4691359]
[7]
Glueck CJ, Scheel D, Fishback J, Steiner P. Progestagens, anabolic-androgenic compounds, estrogens: effects on triglycerides and postheparin lipolytic enzymes. Lipids 1972; 7(2): 110-3.
[http://dx.doi.org/10.1007/BF02532597] [PMID: 4551949]
[8]
Nerbrand C, Nyberg P, Nordström L, Samsioe G. Effects of a lipid lowering fibrate and hormone replacement therapy on serum lipids and lipoproteins in overweight postmenopausal women with elevated triglycerides. Maturitas 2002; 42(1): 55-62.
[http://dx.doi.org/10.1016/S0378-5122(01)00302-4] [PMID: 12020980]
[9]
Stevenson JC, Chines A, Pan K, Ryan KA, Mirkin S. A pooled analysis of the effects of conjugated estrogens/bazedoxifene on lipid parameters in postmenopausal women from the selective estrogens, menopause, and response to therapy (SMART) trials. J Clin Endocrinol Metab 2015; 100(6): 2329-38.
[http://dx.doi.org/10.1210/jc.2014-2649] [PMID: 25894963]
[10]
Garry PJ, Baumgartner RN, Brodie SG, et al. Estrogen replacement therapy, serum lipids, and polymorphism of the apolipoprotein E gene. Clin Chem 1999; 45(8 Pt 1): 1214-23.
[http://dx.doi.org/10.1093/clinchem/45.8.1214] [PMID: 10430787]
[11]
Kota SK, Kota SK, Jammula S, Krishna SV, Modi KD. Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review. Indian J Endocrinol Metab 2012; 16(1): 141-3.
[http://dx.doi.org/10.4103/2230-8210.91211] [PMID: 22276267]
[12]
Afari ME, Shafqat H, Shafi M, Marmoush FY, Roberts MB, Minami T. Hypertriglyceridemia-induced pancreatitis: a decade of experience in a community-based teaching hospital. R I Med J 2015; 98(12): 40-3.
[PMID: 26623455]
[13]
Markell MS, Armenti V, Danovitch G, Sumrani N. Hyperlipidemia and glucose intolerance in the post-renal transplant patient. J Am Soc Nephrol 1994; 4(8): 37-47.
[PMID: 8193294]
[14]
Carr MC, Knopp RH, Brunzell JD, et al. Effect of raloxifene on serum triglycerides in women with a history of hypertriglyceridemia while on oral estrogen therapy. Diabetes Care 2005; 28(7): 1555-61.
[http://dx.doi.org/10.2337/diacare.28.7.1555] [PMID: 15983300]
[15]
Dansuk R, Unal O, Karageyim Y, Esim E, Turan C. Evaluation of the effect of tibolone and transdermal estradiol on triglyceride level in hypertriglyceridemic and normotriglyceridemic postmenopausal women. Gynecol Endocrinol 2004; 18(5): 233-9.
[http://dx.doi.org/10.1080/09513590410001715199] [PMID: 15346658]
[16]
Wójcik C, Fazio S, McIntyre AD, Hegele RA. Co-occurrence of heterozygous CREB3L3 and APOA5 nonsense variants and polygenic risk in a patient with severe hypertriglyceridemia exacerbated by estrogen administration. J Clin Lipidol 2018; 12(5): 1146-50.
[http://dx.doi.org/10.1016/j.jacl.2018.05.014] [PMID: 29954705]
[17]
Dhir R, Brown DK, Olden KW. Drug-induced pancreatitis: a practical review. Drugs Today 2007; 43(7): 499-507.
[http://dx.doi.org/10.1358/dot.2007.43.7.1067339] [PMID: 17728850]
[18]
Mallory A, Kern F Jr. Drug-induced pancreatitis: a critical review. Gastroenterology 1980; 78(4): 813-20.
[http://dx.doi.org/10.1016/0016-5085(80)90689-7] [PMID: 6986321]
[19]
Mallory A, Kern F. Drug-induced pancreatitis. Baillieres Clin Gastroenterol 1988; 2(2): 293-307.
[http://dx.doi.org/10.1016/0950-3528(88)90005-X] [PMID: 3044464]
[20]
Nakashima Y, Howard JM. Drug-induced acute pancreatitis. Surg Gynecol Obstet 1977; 145(1): 105-9.
[PMID: 195355]
[21]
Dobrilla G, Felder M, Chilovi F. [Acute drug-induced pancreatitis]. Schweiz Med Wochenschr 1985; 115(25): 850-8.
[PMID: 3927479]
[22]
Dobrilla G, Felder M, Chilovi F. [Proven relationship between drugs and pancreatitis]. Dtsch Med Wochenschr 1986; 111(22): 868-70.
[http://dx.doi.org/10.1055/s-2008-1068548] [PMID: 3086067]
[23]
Underwood TW, Frye CB. Drug-induced pancreatitis. Clin Pharm 1993; 12(6): 440-8.
[PMID: 8403815]
[24]
Lee J, Goldberg IJ. Hypertriglyceridemia-induced pancreatitis created by oral estrogen and in vitro fertilization ovulation induction. J Clin Lipidol 2008; 2(1): 63-6.
[http://dx.doi.org/10.1016/j.jacl.2007.11.001] [PMID: 19190717]
[25]
Aljenedil S, Hegele RA, Genest J, Awan Z. Estrogen-associated severe hypertriglyceridemia with pancreatitis. J Clin Lipidol 2017; 11(1): 297-300.
[http://dx.doi.org/10.1016/j.jacl.2016.12.006] [PMID: 28391900]
[26]
Medh JD, Fry GL, Bowen SL, Ruben S, Wong H, Chappell DA. Lipoprotein lipase- and hepatic triglyceride lipase- promoted very low density lipoprotein degradation proceeds via an apolipoprotein E-dependent mechanism. J Lipid Res 2000; 41(11): 1858-71.
[PMID: 11060356]
[27]
Dragoman MV, Tepper NK, Fu R, Curtis KM, Chou R, Gaffield ME. A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. Int J Gynaecol Obstet 2018; 141(3): 287-94.
[http://dx.doi.org/10.1002/ijgo.12455] [PMID: 29388678]
[28]
Gourdy P, Bachelot A, Catteau-Jonard S, et al. Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology. Ann Endocrinol (Paris) 2012; 73(5): 469-87.
[http://dx.doi.org/10.1016/j.ando.2012.09.001] [PMID: 23078975]
[29]
de Bastos M, Stegeman BH, Rosendaal FR, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014; 3 CD010813
[PMID: 24590565]
[30]
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280(7): 605-13.
[http://dx.doi.org/10.1001/jama.280.7.605] [PMID: 9718051]
[31]
Schenck-Gustafsson K, Brincat M, Erel CT, et al. EMAS position statement: Managing the menopause in the context of coronary heart disease. Maturitas 2011; 68(1): 94-7.
[http://dx.doi.org/10.1016/j.maturitas.2010.10.005] [PMID: 21156341]
[32]
Herrington DM. The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study. Ann Intern Med 1999; 131(6): 463-6.
[http://dx.doi.org/10.7326/0003-4819-131-6-199909210-00012] [PMID: 10498564]
[33]
Mohandas B, Mehta JL. Lessons from hormone replacement therapy trials for primary prevention of cardiovascular disease. Curr Opin Cardiol 2007; 22(5): 434-42.
[http://dx.doi.org/10.1097/HCO.0b013e328201cb7a] [PMID: 17762545]
[34]
Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017; 1 CD004143
[http://dx.doi.org/10.1002/14651858.CD004143.pub5] [PMID: 28093732]
[35]
Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297(13): 1465-77.
[http://dx.doi.org/10.1001/jama.297.13.1465] [PMID: 17405972]
[36]
Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007; 356(25): 2591-602.
[http://dx.doi.org/10.1056/NEJMoa071513] [PMID: 17582069]
[37]
Leuzzi C, Marzullo R, Modena MG. [Is menopause a risk factor for ischemic heart disease in women?]. G Ital Cardiol (Rome) 2012; 13(6): 401-6.
[PMID: 22622118]
[38]
American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG Committee Opinion No. 420, November 2008: hormone therapy and heart disease. Obstet Gynecol 2008; 112: 1189-92.
[PMID: 18978127]
[39]
Lagranha CJ, Silva TLA, Silva SCA, et al. Protective effects of estrogen against cardiovascular disease mediated via oxidative stress in the brain. Life Sci 2018; 192: 190-8.
[http://dx.doi.org/10.1016/j.lfs.2017.11.043] [PMID: 29191645]
[40]
Komm BS, Thompson JR, Mirkin S. Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. Climacteric 2015; 18(4): 503-11.
[http://dx.doi.org/10.3109/13697137.2014.992011] [PMID: 25511453]
[41]
Lello S, Capozzi A, Scambia G. The tissue-selective estrogen complex (bazedoxifene/conjugated estrogens) for the treatment of menopause. Int J Endocrinol 2017; 2017 5064725
[http://dx.doi.org/10.1155/2017/5064725] [PMID: 29358948]
[42]
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): 350-61.
[http://dx.doi.org/10.1016/j.kjms.2014.03.002] [PMID: 24924841]
[43]
Merlotti C, Morabito A, Pontiroli AE. Prevention of type 2 diabetes; a systematic review and meta-analysis of different intervention strategies. Diabetes Obes Metab 2014; 16(8): 719-27.
[http://dx.doi.org/10.1111/dom.12270] [PMID: 24476122]
[44]
Kim KH, Moriarty K, Bender JR. Vascular cell signaling by membrane estrogen receptors. Steroids 2008; 73(9-10): 864-9.
[http://dx.doi.org/10.1016/j.steroids.2008.01.008] [PMID: 18325557]
[45]
Ryu SK, Mahmud E, Tsimikas S. Estrogen-eluting stents. J Cardiovasc Transl Res 2009; 2(3): 240-4.
[http://dx.doi.org/10.1007/s12265-009-9105-x] [PMID: 19654888]
[46]
Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol 2010; 122(1-3): 42-52.
[http://dx.doi.org/10.1016/j.jsbmb.2009.12.010] [PMID: 20036327]
[47]
Jing Z, Liang-Zhi X, Tai-Xiang W, Ying T, Yu-Jian J. The effects of Diane-35 and metformin in treatment of polycystic ovary syndrome: an updated systematic review. Gynecol Endocrinol 2008; 24(10): 590-600.
[http://dx.doi.org/10.1080/09513590802288242] [PMID: 19012104]
[48]
Cahill DJ, O’Brien K. Polycystic ovary syndrome (PCOS): metformin. BMJ Clin Evid 2015 2015. pii: 1408
[PMID: 25814168]
[49]
Roach RE, Helmerhorst FM, Lijfering WM, Stijnen T, Algra A, Dekkers OM. Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev 2015; 8 CD011054
[http://dx.doi.org/10.1002/14651858.CD011054.pub2] [PMID: 26310586]
[50]
Villa A, Vegeto E, Poletti A, Maggi A. Estrogens, neuroinflammation, and neurodegeneration. Endocr Rev 2016; 37(4): 372-402.
[http://dx.doi.org/10.1210/er.2016-1007] [PMID: 27196727]
[51]
Scott E, Zhang QG, Wang R, Vadlamudi R, Brann D. Estrogen neuroprotection and the critical period hypothesis. Front Neuroendocrinol 2012; 33(1): 85-104.
[http://dx.doi.org/10.1016/j.yfrne.2011.10.001] [PMID: 22079780]
[52]
Billeci AM, Paciaroni M, Caso V, Agnelli G. Hormone replacement therapy and stroke. Curr Vasc Pharmacol 2008; 6(2): 112-23.
[http://dx.doi.org/10.2174/157016108783955338] [PMID: 18393913]
[53]
Cassidy A, Hooper L. Phytoestrogens and cardiovascular disease. J Br Menopause Soc 2006; 12(2): 49-56.
[http://dx.doi.org/10.1258/136218006777525776] [PMID: 16776855]
[54]
Tempfer CB, Bentz EK, Leodolter S, et al. Phytoestrogens in clinical practice: a review of the literature. Fertil Steril 2007; 87(6): 1243-9.
[http://dx.doi.org/10.1016/j.fertnstert.2007.01.120] [PMID: 17490659]
[55]
Goodman MP. Are all estrogens created equal? A review of oral vs. transdermal therapy. J Womens Health 2012; 21(2): 161-9.
[http://dx.doi.org/10.1089/jwh.2011.2839] [PMID: 22011208]
[56]
Rovinski D, Ramos RB, Fighera TM, Casanova GK, Spritzer PM. Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis. Thromb Res 2018; 168: 83-95.
[http://dx.doi.org/10.1016/j.thromres.2018.06.014] [PMID: 29936403]
[57]
Tepper NK, Dragoman MV, Gaffield ME, Curtis KM. Nonoral combined hormonal contraceptives and thromboembolism: a systematic review. Contraception 2017; 95(2): 130-9.
[http://dx.doi.org/10.1016/j.contraception.2016.10.005] [PMID: 27771476]
[58]
Stojanovic ND, Kwong P, Byrne DJ, et al. The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study. Angiology 2003; 54(4): 391-9.
[http://dx.doi.org/10.1177/000331970305400402] [PMID: 12934758]
[59]
Bezwada P, Shaikh A, Misra D. The effect of transdermal estrogen patch use on cardiovascular outcomes: a systematic review. J Womens Health (Larchmt) 2017; 26(12): 1319-25.
[http://dx.doi.org/10.1089/jwh.2016.6151] [PMID: 28622476]
[60]
Speroff L. Transdermal hormone therapy and the risk of stroke and venous thrombosis. Climacteric 2010; 13(5): 429-32.
[http://dx.doi.org/10.3109/13697137.2010.507111] [PMID: 20670199]
[61]
Formoso G, Perrone E, Maltoni S, et al. Short-term and long-term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev 2016. 10CD008536
[http://dx.doi.org/10.1002/14651858.CD008536.pub3] [PMID: 27733017]
[62]
Formoso G, Perrone E, Maltoni S, et al. Short and long term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev 2012; 2 CD008536
[http://dx.doi.org/10.1002/14651858.CD008536.pub2] [PMID: 22336846]
[63]
Creatsas G, Christodoulakos G, Lambrinoudaki I, Panoulis C, Chondros C, Patramanis P. Serum lipids and apolipoproteins in Greek postmenopausal women: association with estrogen, estrogen-progestin, tibolone and raloxifene therapy. J Endocrinol Invest 2003; 26(6): 545-51.
[http://dx.doi.org/10.1007/BF03345218] [PMID: 12952369]
[64]
Christodoulakos GE, Lambrinoudaki IV, Panoulis CP, Papadias CA, Kouskouni EE, Creatsas GC. Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women. Gynecol Endocrinol 2004; 18(5): 244-57.
[http://dx.doi.org/10.1080/09513590410001715207] [PMID: 15346660]
[65]
Koh KK, Han SH, Shin MS, Ahn JY, Lee Y, Shin EK. Significant differential effects of lower doses of hormone therapy or tibolone on markers of cardiovascular disease in post-menopausal women: a randomized, double-blind, crossover study. Eur Heart J 2005; 26(14): 1362-8.
[http://dx.doi.org/10.1093/eurheartj/ehi311] [PMID: 15872028]
[66]
Freitas AK, Freitas RA Jr, Prado MF, et al. [Tibolone treatment of diabetic postmenopausal women: clinical and laboratory safety parameters]. Arq Bras Endocrinol Metabol 2005; 49(3): 433-40.
[http://dx.doi.org/10.1590/S0004-27302005000300016] [PMID: 16543999]
[67]
Christodoulakos GE, Lambrinoudaki IV, Economou EV, et al. Differential effect of hormone therapy and tibolone on lipids, lipoproteins, and the atherogenic index of plasma. J Cardiovasc Pharmacol 2006; 47(4): 542-8.
[http://dx.doi.org/10.1097/01.fjc.0000211747.16573.d5] [PMID: 16680067]
[68]
Traianos A, Vavilis D, Makedos A, et al. Effect of short-term tibolone treatment on risk markers for cardiovascular disease in healthy postmenopausal women: a randomized controlled study. Clin Exp Obstet Gynecol 2013; 40(4): 542-5.
[PMID: 24597251]
[69]
Prelevic GM, Kwong P, Byrne DJ, Jagroop IA, Ginsburg J, Mikhailidis DP. A cross-sectional study of the effects of hormon replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women. Fertil Steril 2002; 77(5): 945-51.
[http://dx.doi.org/10.1016/S0015-0282(02)03078-9] [PMID: 12009348]
[70]
Ostberg JE, Damjanovic T, Dimkovic N, Byrne D, Mikhailidis DP, Prelevic GM. Effect of tibolone on markers of cardiovascular disease risk in postmenopausal women undergoing hemodialysis: a pilot study. Fertil Steril 2004; 81(6): 1624-31.
[http://dx.doi.org/10.1016/j.fertnstert.2003.11.033] [PMID: 15193486]
[71]
Gallo MA, Kaufman D. Antagonistic and agonistic effects of tamoxifen: significance in human cancer. Semin Oncol 1997; 24: S1-71.
[PMID: 9045319]
[72]
Mikhailidis D, Ganotakis E, Georgoulias V, Vallance D, Winder A. Tamoxifen-induced hypertriglyceridaemia. Oncol Rep 1997; 4(3): 625-8.
[PMID: 21590112]
[73]
Singh HK, Prasad MS, Kandasamy AK, Dharanipragada K. Tamoxifen-induced hypertriglyceridemia causing acute pancreatitis. J Pharmacol Pharmacother 2016; 7(1): 38-40.
[http://dx.doi.org/10.4103/0976-500X.179365] [PMID: 27127396]
[74]
Filippatos TD, Liberopoulos EN, Pavlidis N, Elisaf MS, Mikhailidis DP. Effects of hormonal treatment on lipids in patients with cancer. Cancer Treat Rev 2009; 35(2): 175-84.
[http://dx.doi.org/10.1016/j.ctrv.2008.09.007] [PMID: 19013720]
[75]
Markopoulos C, Chrissochou M, Antonopoulou Z, et al. Duration of tamoxifen effect on lipidemic profile of postmenopausal breast cancer patients following deprivation of treatment. Oncology 2006; 70(4): 301-5.
[http://dx.doi.org/10.1159/000096251] [PMID: 17047401]
[76]
Garcia-Rios A, Leon-Acuna A, Lopez-Miranda J, Perez-Martinez P. Lipoprotein (a) management: lifestyle and hormones. Curr Med Chem 2017; 24(10): 979-88.
[http://dx.doi.org/10.2174/0929867324666170124144427] [PMID: 28120711]
[77]
Sahebkar A, Serban MC, Penson P, et al. The effects of tamoxifen on plasma lipoprotein(a) concentrations: systematic review and meta-analysis. Drugs 2017; 77(11): 1187-97.
[http://dx.doi.org/10.1007/s40265-017-0767-4] [PMID: 28573436]

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