Login Register Cart 0
Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Menopause and Non-Alcoholic Fatty Liver Disease: A Review Focusing on Therapeutic Perspectives

Author(s): Vasiliki Venetsanaki and Stergios A. Polyzos*

Volume 17, Issue 6, 2019

Page: [546 - 555] Pages: 10

DOI: 10.2174/1570161116666180711121949

Price: $65

conference banner
Abstract

There is increasing evidence that menopause is associated with the progression and severity of non-alcoholic fatty liver disease (NAFLD). Estrogen deficiency worsens non-alcoholic steatohepatitis (NASH) in mice models with fatty liver. The prevalence of NAFLD seems to be higher in postmenopausal compared with premenopausal women. Although more data are needed, lower serum estradiol levels are associated with NASH in postmenopausal women. Apart from estrogen deficiency, relative androgen excess and decrease in sex hormone-binding protein are observed in postmenopausal women. These hormonal changes seem to interplay with an increase in abdominal adipose mass, also observed in postmenopausal women, and aging, which are both closely related to the severity and progressive forms of NAFLD. NAFLD adds extra morbidity to postmenopausal women, possibly increasing the risk of type 2 diabetes mellitus and cardiovascular disease. Improving parameters of the metabolic syndrome via modifications in diet and physical exercise may reduce the risk of NAFLD and its related morbidity. Limited studies have shown a beneficial effect of hormone replacement therapy (HRT) on NAFLD, although adverse hepatic effects have been attributed to progesterone in one study. Phytoestrogens may be alternatives to HRT, but their long-term efficacy and safety remain to be shown. The aim of this review was to summarize evidence linking menopause with NAFLD with a special focus on potential therapeutic perspectives.

Keywords: Estrogens, menopause, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, sex hormone-binding globulin, steatosis, testosterone.

« Previous Next »
Graphical Abstract

[1]
Fazel Y, Koenig AB, Sayiner M, Goodman ZD, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism 2016; 65(8): 1017-25.
[2]
Khan RS, Newsome PN. Non-alcoholic fatty liver disease and liver transplantation. Metabolism 2016; 65(8): 1208-23.
[3]
Polyzos S, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: The pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med 2009; 9(3): 299-314.
[4]
Rinella ME. Nonalcoholic fatty liver disease. JAMA 2015; 313(22): 2263.
[5]
Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: An update. Metabolism 2016; 65(8): 1109-23.
[6]
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia 2016; 59(6): 1121-40.
[7]
Polyzos SA, Kountouras J, Zavos C, Deretzi G. Nonalcoholic fatty liver disease. J Clin Gastroenterol 2012; 46(4): 272-84.
[8]
Gutierrez-Grobe Y, Ponciano-Rodríguez G, Ramos MH, Uribe M, Méndez-Sánchez N. Prevalence of non alcoholic fatty liver disease in premenopausal, posmenopausal and polycystic ovary syndrome women. The role of estrogens. Ann Hepatol 2010; 9(4): 402-9.
[9]
Polyzos SA, Kountouras J, Tsatsoulis A, et al. Sex steroids and sex hormone-binding globulin in postmenopausal women with nonalcoholic fatty liver disease. Hormones (Athens) 2013; 12(3): 405-16.
[10]
Kamada Y, Kiso S, Yoshida Y, et al. Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet. Am J Physiol Liver Physiol 2011; 301(6): 1031-43.
[11]
McKenzie J, Fisher BM, Jaap AJ, Stanley A, Paterson K, Sattar N. Effects of HRT on liver enzyme levels in women with type 2 diabetes: A randomized placebo-controlled trial. Clin Endocrinol (Oxf) 2006; 65(1): 40-4.
[12]
Polyzos SA, Kountouras J, Zavos C. The multi-hit process and the antagonistic roles of tumor necrosis factor-alpha and adiponectin in non alcoholic fatty liver disease. Hippokratia 2009; 13(2): 127.
[13]
Itagaki T, Shimizu I, Cheng X, et al. Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells. Gut 2005; 54(12): 1782-9.
[14]
Shimizu I, Mizobuchi Y, Yasuda M, et al. Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro. Gut 1999; 44(1): 127-36.
[15]
Yasuda M, Shimizu I, Shiba M, Ito S. Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. Hepatology 1999; 29(3): 719-27.
[16]
Lax ER, Tamulevicius P, Müller A, Schriefers H. Hepatic nuclear estrogen receptor concentrations in the rat-influence of age, sex, gestation, lactation and estrous cycle. J Steroid Biochem 1983; 19(2): 1083-8.
[17]
Shen M, Shi H. Sex hormones and their receptors regulate liver energy homeostasis. Int J Endocrinol 2015; 2015: 1-12.
[18]
Fisher CR, Graves KH, Parlow AF, Simpson ER. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci USA 1998; 95(12): 6965-70.
[19]
Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 2000; 97(23): 12735-40.
[20]
Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor-α knockout mice. Proc Natl Acad Sci USA 2000; 97(23): 12729-34.
[21]
Paquette A, Wang D, Jankowski M, Gutkowska J, Lavoie J-M. Effects of ovariectomy on PPARα, SREBP-1c, and SCD-1 gene expression in the rat liver. Menopause 2008; 15(6): 1169-75.
[22]
Paquette A, Shinoda M, Lhoret RR, Prud’homme D, Lavoie J-M. Time course of liver lipid infiltration in ovariectomized rats: Impact of a high-fat diet. Maturitas 2007; 58(2): 182-90.
[23]
Barsalani R, Pighon A, Rabasa-Lhoret R, Yasari S, Lavoie J-M. Liver of ovariectomized rats is resistant to resorption of lipids. Physiol Behav 2008; 95(1-2): 216-21.
[24]
Corriveau P, Paquette A, Brochu M, Prud’homme D, Rabasa-Lhoret R, Lavoie J-M. Resistance training prevents liver fat accumulation in ovariectomized rats. Maturitas 2008; 59(3): 259-67.
[25]
Domingos MM, Rodrigues MFC, Stotzer US, et al. Resistance training restores the gene expression of molecules related to fat oxidation and lipogenesis in the liver of ovariectomized rats. Eur J Appl Physiol 2012; 112(4): 1437-44.
[26]
Pighon A, Gutkowska J, Jankowski M, Rabasa-Lhoret R, Lavoie J-M. Exercise training in ovariectomized rats stimulates estrogenic-like effects on expression of genes involved in lipid accumulation and subclinical inflammation in liver. Metabolism 2011; 60(5): 629-39.
[27]
Nemoto Y, Toda K, Ono M, et al. Altered expression of fatty acid-metabolizing enzymes in aromatase-deficient mice. J Clin Invest 2000; 105(12): 1819-25.
[28]
D’Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS. Estrogen regulation of adiposity and fuel partitioning. J Biol Chem 2005; 280(43): 35983-91.
[29]
Fu X, Xing L, Xu W, Shu J. Treatment with estrogen protects against ovariectomy-induced hepatic steatosis by increasing AQP7 expression. Mol Med Rep 2016; 14(1): 425-31.
[30]
Zhu L, Brown WC, Cai Q, et al. Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes 2013; 62(2): 424-34.
[31]
Luo F, Ishigami M, Achiwa K, et al. Raloxifene ameliorates liver fibrosis of nonalcoholic steatohepatitis induced by choline-deficient high-fat diet in ovariectomized mice. Dig Dis Sci 2015; 60(9): 2730-9.
[32]
Panneerselvam S, Packirisamy RM, Bobby Z, Elizabeth JS, Sridhar MG. Soy isoflavones (Glycine max) ameliorate hypertriglyceridemia and hepatic steatosis in high fat-fed ovariectomized Wistar rats (an experimental model of postmenopausal obesity). J Nutr Biochem 2016; 38: 57-69.
[33]
Choi JS, Song J. Effect of genistein on insulin resistance, renal lipid metabolism, and antioxidative activities in ovariectomized rats. Nutrition 2009; 25(6): 676-85.
[34]
Kim MH, Park JS, Jung JW, Byun KW, Kang KS, Lee YS. Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism. Int J Obes 2011; 35(8): 1019-30.
[35]
Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002; 122(6): 1649-57.
[36]
Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12 years: Analysis of clinical background. J Gastroenterol 2003; 38(10): 954-61.
[37]
Park Sh, Jeon Wk, Kim Sh, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 2006; 21(1): 138-43.
[38]
Völzke H, Schwarz S, Baumeister SE, et al. Menopausal status and hepatic steatosis in a general female population. Gut 2007; 56(4): 594-5.
[39]
Bruno A de S, Rodrigues MH, Alvares MCB, Nahas-Neto J, Nahas EAP. Non-alcoholic fatty liver disease and its associated risk factors in Brazilian postmenopausal women. Climacteric 2014; 17(4): 465-71.
[40]
Wang Z, Xu M, Hu Z, Shrestha UK. Prevalence of nonalcoholic fatty liver disease and its metabolic risk factors in women of different ages and body mass index. Menopause 2015; 22(6): 667-73.
[41]
Söderberg C, Stål P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51(2): 595-602.
[42]
Yang JD, Abdelmalek MF, Pang H, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 2014; 59(4): 1406-14.
[43]
Yoneda M, Thomas E, Sumida Y, Eguchi Y, Schiff ER. The influence of menopause on the development of hepatic fibrosis in nonobese women with nonalcoholic fatty liver disease. Hepatology 2014; 60(5): 1792.
[44]
Polyzos SA, Mantzoros CS. Nonalcoholic fatty future disease. Metabolism 2016; 65(8): 1007-16.
[45]
Lu J, Zhang J, Du R, et al. Age at menarche is associated with the prevalence of non-alcoholic fatty liver disease later in life. J Diabetes 2017; 9(1): 53-60.
[46]
Mueller NT, Pereira MA, Demerath EW, et al. Earlier menarche is associated with fatty liver and abdominal ectopic fat in midlife, independent of young adult BMI: The CARDIA study. Obesity (Silver Spring) 2015; 23(2): 468-74.
[47]
Klair JS, Yang JD, Abdelmalek MF, et al. A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatology 2016; 64(1): 85-91.
[48]
Matsuo K, Gualtieri MR, Cahoon SS, et al. Surgical menopause and increased risk of nonalcoholic fatty liver disease in endometrial cancer. Menopause 2016; 23(2): 189-96.
[49]
Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S. Tamoxifen-induced fatty liver in patients with breast cancer. Lancet 1998; 351(9104): 725.
[50]
Bruno S, Maisonneuve P, Castellana P, et al. Incidence and risk factors for non-alcoholic steatohepatitis: Prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005; 330(7497): 932.
[51]
Nemoto Y, Saibara T, Ogawa Y, et al. Tamoxifen-induced nonalcoholic steatohepatitis in breast cancer patients treated with adjuvant tamoxifen. Intern Med 2002; 41(5): 345-50.
[52]
Ogawa Y, Murata Y, Saibara T, Nishioka A, Kariya S, Yoshida S. Follow-up CT findings of tamoxifen-induced non-alcoholic steatohepatitis (NASH) of breast cancer patients treated with bezafibrate. Oncol Rep 2003; 10(5): 1473-8.
[53]
Elefsiniotis IS, Pantazis KD, Ilias A, et al. Tamoxifen induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: The role of glucose intolerance. Eur J Gastroenterol Hepatol 2004; 16(6): 593-8.
[54]
Moffat DF, Oien KA, Dickson J, Habeshaw T, McLellan DR. Hepatocellular carcinoma after long-term tamoxifen therapy. Ann Oncol 2000; 11(9): 1195-6.
[55]
Pratt DS, Knox TA, Erban J. Tamoxifen-induced steatohepatitis. Ann Intern Med 1995; 123(3): 236.
[56]
Oien KA, Moffat D, Curry GW, et al. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 1999; 353(9146): 36-7.
[57]
Rosner W. The functions of corticosteroid-binding globulin and sex hormone-binding globulin: Recent Advances. Endocr Rev 1990; 11(1): 80-91.
[58]
Pasquali R, Vicennati V, Bertazzo D, et al. Determinants of sex hormone-binding globulin blood concentrations in premenopausal and postmenopausal women with different estrogen status. Metabolism 1997; 46(1): 5-9.
[59]
Hua X, Li M, Pan F, Xiao Y, Cui W, Hu Y. Non-alcoholic fatty liver disease is an influencing factor for the association of SHBG with metabolic syndrome in diabetes patients. Sci Rep 2017; 7(1): 14532.
[60]
Ye J, Yao Z, Tan A, et al. Low serum sex hormone-binding globulin associated with insulin resistance in men with nonalcoholic fatty liver disease. Horm Metab Res 2017; 49(5): 359-64.
[61]
Jaruvongvanich V, Sanguankeo A, Riangwiwat T, Upala S. Testosterone, sex hormone-binding globulin and nonalcoholic fatty liver disease: A systematic review and meta-analysis. Ann Hepatol 2017; 16(3): 382-94.
[62]
Lazo M, Zeb I, Nasir K, et al. Association between endogenous sex hormones and liver fat in a multiethnic study of atherosclerosis. Clin Gastroenterol Hepatol 2015; 13(9): 1686-93.
[63]
Klisic A, Kavaric N, Jovanovic M, Soldatovic I, Gligorovic-Barhanovic N, Kotur-Stevuljevic J. Bioavailable testosterone is independently associated with fatty liver index in postmenopausal women. Arch Med Sci 2017; 5(5): 1188-96.
[64]
Sarkar M, Wellons M, Cedars MI, et al. Testosterone levels in pre-menopausal women are associated with nonalcoholic fatty liver disease in midlife. Am J Gastroenterol 2017; 112(5): 755-62.
[65]
Vassilatou E. Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J Gastroenterol 2014; 20(26): 8351-63.
[66]
Polyzos S, Goulis D, Kountouras J, et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: Assessment of non-invasive indices predicting hepatic steatosis and fibrosis. Hormones 2014; 13(4): 519-31.
[67]
Suzuki A, Abdelmalek MF. nonalcoholic fatty liver disease in women. Women Health 2009; 5(2): 191-203.
[68]
Rocha ALL, Faria LC, Guimarães TCM, et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: Systematic review and meta-analysis. J Endocrinol Invest 2017; 40(12): 1279-88.
[69]
Mccullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol 2006; 40: 17-29.
[70]
Polyzos SA, Kountouras J, Mantzoros CS. Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol 2017; 42(2): 92-108.
[71]
Park Y-W, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: Prevalence and associated risk factor findings in the US population from the third national health and nutrition examination survey, 1988-1994. Arch Intern Med 2003; 163(4): 427-36.
[72]
Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003; 88(6): 2404-11.
[73]
Lindheim SR, Buchanan TA, Duffy DM, et al. Comparison of estimates of insulin sensitivity in pre- and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test. J Soc Gynecol Investig 1994; 1(2): 150-4.
[74]
Walton C, Godsland IF, Proudler AJ, Wynn V, Stevenson JC. The effects of the menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. Eur J Clin Invest 1993; 23(8): 466-73.
[75]
Kim S, Choi J, Kim M. Insulin resistance, inflammation, and nonalcoholic fatty liver disease in non-obese adults without metabolic syndrome components. Hepatol Int 2013; 7(2): 586-91.
[76]
Bitoska I, Krstevska B, Milenkovic T, et al. Effects of hormone replacement therapy on insulin resistance in postmenopausal diabetic women. Open Access Maced J Med Sci 2016; 4(1): 83-8.
[77]
Brussaard HE, Gevers Leuven JA, Frölich M, Kluft C, Krans HM. Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia 1997; 40(7): 843-9.
[78]
Mintziori G, Polyzos SA. Emerging and future therapies for nonalcoholic steatohepatitis in adults. Expert Opin Pharmacother 2016; 17(14): 1937-46.
[79]
Said A, Akhter A. Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis. Ann Hepatol 2017; 16(4): 538-47.
[80]
Polyzos SA, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: A systematic review. Metabolism 2016; 65(9): 1297-306.
[81]
Katsagoni CN, Georgoulis M, Papatheodoridis GV, Panagiotakos DB, Kontogianni MD. Effects of lifestyle interventions on clinical characteristics of patients with non-alcoholic fatty liver disease: A meta-analysis. Metabolism 2017; 68: 119-32.
[82]
Orci LA, Gariani K, Oldani G, Delaune V, Morel P, Toso C. Exercise-based interventions for nonalcoholic fatty liver disease: A meta-analysis and meta-regression. Clin Gastroenterol Hepatol 2016; 14(10): 1398-411.
[83]
Otten J, Mellberg C, Ryberg M, et al. Strong and persistent effect on liver fat with a paleolithic diet during a two-year intervention. Int J Obes 2016; 40(5): 747-53.
[84]
Parker HM, Johnson NA, Burdon CA, Cohn JS, O’Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Hepatol 2012; 56(4): 944-51.
[85]
Rezende REF, Duarte SMB, Stefano JT, et al. Randomized clinical trial: benefits of aerobic physical activity for 24 weeks in postmenopausal women with nonalcoholic fatty liver disease. Menopause 2016; 23(8): 876-83.
[86]
Cheng S, Ge J, Zhao C, et al. Effect of aerobic exercise and diet on liver fat in pre-diabetic patients with non-alcoholic-fatty-liver-disease: A randomized controlled trial. Sci Rep 2017; 7(1): 15952.
[87]
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA 2013; 310(13): 1353.
[88]
Florentino Gs de A, Cotrim Hp, Vilar Cp, Florentino Av de A, Guimaraes Gma, Barreto Vst. Nonalcoholic fatty liver disease in menopausal women. Arq Gastroenterol 2013; 50(3): 180-5.
[89]
Yang JD, Abdelmalek MF, Guy CD, et al. Patient sex, reproductive status, and synthetic hormone use associate with Histologic severity of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2017; 15(1): 127-31.
[90]
Barsalani R, Riesco E, Lavoie J-M, Dionne IJ. Effect of exercise training and isoflavones on hepatic steatosis in overweight postmenopausal women. Climacteric 2013; 16(1): 88-95.
[91]
Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017; 66(6): 1138-53.
[92]
Upala S, Jaruvongvanich V, Wijarnpreecha K, Sanguankeo A. Nonalcoholic fatty liver disease and osteoporosis: A systematic review and meta-analysis. J Bone Miner Metab 2017; 35(6): 685-93.
[93]
Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev 2013; 12CD008623
[94]
Kargiotis K, Athyros VG, Giouleme O, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol 2015; 21(25): 7860.
[95]
Athyros VG, Alexandrides TK, Bilianou H, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement. Metabolism 2017; 71: 17-32.
[96]
Giannitrapani L, Soresi M, LaSpada E, Cervello M, D’Alessandro N, Montalto G. Sex hormones and risk of liver tumor. Ann N Y Acad Sci 2006; 1089(1): 228-36.
[97]
Polyzos SA, Goulis DG, Kountouras J. Nonalcoholic fatty liver disease and polycystic ovary syndrome. Ann Hepatol 2015; 14(6): 941-3.
[98]
Sporea I, Popescu A, Sirli R. Why, who and how should perform liver biopsy in chronic liver diseases. World J Gastroenterol 2008; 14(21): 3396.
[99]
Polyzos SA, Mantzoros CS. Necessity for timely noninvasive diagnosis of nonalcoholic fatty liver disease. Metabolism 2014; 63(2): 161-7.
[100]
Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers. J Hepatol 2018; 68(2): 305-15.

Rights & Permissions Print Cite
Article Metrics
151
17
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy