收稿日期: 2022-05-29
录用日期: 2022-09-28
网络出版日期: 2022-12-19
基金资助
上海交通大学医学院附属第六人民医院院级科学研究基金（X-院内-2258）
Research progress in the correlation and treatment of menopause and non-alcoholic fatty liver disease in women
Received date: 2022-05-29
Accepted date: 2022-09-28
Online published: 2022-12-19
Supported by
Scientific Foundation of Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine(X-hospital-2258)
非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）是慢性非传染性疾病，是代谢综合征（metabolic syndrome，MS）在肝脏的表现。绝经是女性因卵巢功能衰退所呈现的生理现象，表现为下丘脑-垂体功能退化。临床和流行病学研究表明，NAFLD的发病趋势具有两性差异，且与血糖、血脂、血尿酸等代谢参数有关。女性绝经前NAFLD发病率低于男性，而绝经后NAFLD的发病率逐渐升高至与男性相当，其机制可能主要与女性绝经后体内性激素的变化（以雌激素的下降为主）有关。性激素的变化，如雌激素和性激素结合球蛋白（sex hormone binding globulin，SHBG）水平降低而雄激素水平相对升高，会增加腹型肥胖、血脂代谢异常及胰岛素抵抗（insulin resistance，IR）等异常指标的发生率，使绝经成为女性NAFLD的重要的独立危险因素；而雄激素受体拮抗剂、雌激素及植物雌激素等可通过多种途径改善肝脏脂肪变性及IR，减轻NAFLD的严重程度，延缓肝纤维化进展，对绝经女性NAFLD有一定治疗意义，但也具有部分局限性。该文就近年来女性绝经与NAFLD相关关系的研究进展予以综述，为绝经女性NAFLD的预防和治疗提供思路和参考。
刘薇薇 , 王龙 . 女性绝经与非酒精性脂肪性肝病的关系及相关治疗的研究进展[J]. 上海交通大学学报（医学版）, 2023 , 43(1) : 125 -131 . DOI: 10.3969/j.issn.1674-8115.2023.01.017
Non-alcoholic fatty liver disease (NAFLD) is a chronic non-communicable disease. It is a metabolic syndrome (MS) in the liver. Menopause is a physiological phenomenon of women due to the decline of ovarian function, which is characterized by the deterioration of hypothalamic-pituitary function. Clinical and epidemiological studies have shown that the incidence trend of NAFLD has gender differences and is related to metabolic parameters such as glucose, lipids, and blood uric acid. The incidence of NAFLD in premenopausal women is lower than that in males, while the incidence of NAFLD in postmenopausal women gradually increases to the same as that in males. The mechanism may be mainly related to the changes of sex hormones in postmenopausal women (mainly the decrease of estrogen). The changes of sex hormones such as the decreased levels of estrogen and sex hormone binding globulin (SHBG) and the relatively increased level of androgen can increase the incidence of MS components such as abdominal obesity, abnormal blood lipid metabolism and insulin resistance (IR), making menopause an important independent risk factor for NAFLD in women. Estrogen, androgen receptor antagonists and phytoestrogens can improve hepatic steatosis and IR through many ways, reduce the severity of NAFLD and delay its progression to liver fibrosis, which have certain therapeutic significance for postmenopausal women with NAFLD, but also have some limitations. This paper reviews the research progress in the relationship between menopause and NAFLD in recent years, so as to provide ideas and reference for the prevention and treatment of NAFLD in postmenopausal women.
| 1 | LOOMBA R, FRIEDMAN S L, SHULMAN G I. Mechanisms and disease consequences of nonalcoholic fatty liver disease[J]. Cell, 2021, 184(10): 2537-2564. |
| 2 | WANG Z L, XU M, HU Z G, et al. Sex-specific prevalence of fatty liver disease and associated metabolic factors in Wuhan, south central China[J]. Eur J Gastroenterol Hepatol, 2014, 26(9): 1015-1021. |
| 3 | LONG M T, PEDLEY A, MASSARO J M, et al. A simple clinical model predicts incident hepatic steatosis in a community-based cohort: the Framingham Heart Study[J]. Liver Int, 2018, 38(8): 1495-1503. |
| 4 | ARSHAD T, GOLABI P, PAIK J, et al. Prevalence of nonalcoholic fatty liver disease in the female population[J]. Hepatol Commun, 2018, 3(1): 74-83. |
| 5 | KLAIR J S, YANG J D, ABDELMALEK M F, et al. A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease[J]. Hepatology, 2016, 64(1): 85-91. |
| 6 | PARK S H, PARK Y E, LEE J, et al. Lack of association between early menopause and non-alcoholic fatty liver disease in postmenopausal women[J]. Climacteric, 2020, 23(2): 173-177. |
| 7 | JABALLAH A, SOLTANI I, BAHIA W, et al. The relationship between menopause and metabolic syndrome: experimental and bioinformatics analysis[J]. Biochem Genet, 2021, 59(6): 1558-1581. |
| 8 | MUMUSOGLU S, YILDIZ B O. Metabolic syndrome during menopause[J]. Curr Vasc Pharmacol, 2019, 17(6): 595-603. |
| 9 | CHUNG S I, RYU S N, KANG M Y. Changes in bone metabolism and antioxidant defense systems in menopause-induced rats fed bran extract from dark purple rice (Oryza sativa L. Cv. Superjami)[J]. Nutrients, 2021, 13(9): 2926. |
| 10 | DUPUIS M L, PAGANO M T, PIERDOMINICI M, et al. The role of vitamin D in autoimmune diseases: could sex make the difference?[J]. Biol Sex Differ, 2021, 12(1): 12. |
| 11 | MELGUIZO-RODRíGUEZ L, COSTELA-RUIZ V J, GARCíA-RECIO E, et al. Role of vitamin D in the metabolic syndrome[J]. Nutrients, 2021, 13(3): 830. |
| 12 | WAN H, ZHANG K, WANG Y Y, et al. The associations between gonadal hormones and serum uric acid levels in men and postmenopausal women with diabetes[J]. Front Endocrinol (Lausanne), 2020, 11: 55. |
| 13 | WANG X H, JIANG W R, ZHANG M Y, et al. The visceral fat area to leg muscle mass ratio is significantly associated with the risk of hyperuricemia among women: a cross-sectional study[J]. Biol Sex Differ, 2021, 12(1): 17. |
| 14 | 刘勤, 牛春燕. 由“二次打击”到“多重打击”: 发病机制的演变带给非酒精性脂肪性肝病的治疗启示[J]. 世界华人消化杂志, 2019, 27(19): 1171-1178. |
| 14 | LIU Q, NIU C Y. From "two hit theory" to "multiple hit theory": implications of evolution of pathogenesis concepts for treatment of non-alcoholic fatty liver disease[J]. World Chinese Journal of Digestology, 2019, 27(19): 1171-1178. |
| 15 | YARIBEYGI H, FARROKHI F R, BUTLER A E, et al. Insulin resistance: review of the underlying molecular mechanisms[J]. J Cell Physiol, 2019, 234(6): 8152-8161. |
| 16 | VENETSANAKI V, POLYZOS S A. Menopause and non-alcoholic fatty liver disease: a review focusing on therapeutic perspectives[J]. Curr Vasc Pharmacol, 2019, 17(6): 546-555. |
| 17 | WHITCROFT S, HERRIOT A. Insulin resistance and management of the menopause: a clinical hypothesis in practice[J]. Menopause Int, 2011, 17(1): 24-28. |
| 18 | DE MUTSERT R, GAST K, WIDYA R, et al. Associations of abdominal subcutaneous and visceral fat with insulin resistance and secretion differ between men and women: the Netherlands epidemiology of obesity study[J]. Metab Syndr Relat Disord, 2018, 16(1): 54-63. |
| 19 | ZENG X, XIE Y J, LIU Y T, et al. Polycystic ovarian syndrome: correlation between hyperandrogenism, insulin resistance and obesity[J]. Clin Chim Acta, 2020, 502: 214-221. |
| 20 | SEIDU T, MCWHORTER P, MYER J, et al. DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice[J]. J Endocrinol, 2021, 250(2): 49-65. |
| 21 | WANG J, WU D C, GUO H, et al. Hyperandrogenemia and insulin resistance: the chief culprit of polycystic ovary syndrome[J]. Life Sci, 2019, 236: 116940. |
| 22 | KUR P, KOLASA-WO?OSIUK A, MISIAKIEWICZ-HAS K, et al. Sex hormone-dependent physiology and diseases of liver[J]. Int J Environ Res Public Health, 2020, 17(8): 2620. |
| 23 | DELLA T S. Beyond the x factor: relevance of sex hormones in NAFLD pathophysiology[J]. Cells, 2021, 10(9): 2502. |
| 24 | XIA F Z, XU X, ZHAI H L, et al. Castration-induced testosterone deficiency increases fasting glucose associated with hepatic and extra-hepatic insulin resistance in adult male rats[J]. Reprod Biol Endocrinol, 2013, 11: 106. |
| 25 | QU X Q, DONNELLY R. Sex hormone-binding globulin (SHBG) as an early biomarker and therapeutic target in polycystic ovary syndrome[J]. Int J Mol Sci, 2020, 21(21): 8191. |
| 26 | SOWERS M, DERBY C, JANNAUSCH M L, et al. Insulin resistance, hemostatic factors, and hormone interactions in pre- and perimenopausal women: SWAN[J]. J Clin Endocrinol Metab, 2003, 88(10): 4904-4910. |
| 27 | YAMAZAKI H, KUSHIYAMA A, SAKODA H, et al. Protective effect of sex hormone-binding globulin against metabolic syndrome: in vitro evidence showing anti-inflammatory and lipolytic effects on adipocytes and macrophages[J]. Mediators Inflamm, 2018, 2018: 3062319. |
| 28 | DISTEFANO J K. NAFLD and NASH in postmenopausal women: implications for diagnosis and treatment[J]. Endocrinology, 2020, 161(10): bqaa134. |
| 29 | YANG M, LIU Q L, HUANG T L, et al. Dysfunction of estrogen-related receptor α-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development[J]. Theranostics, 2020, 10(24): 10874-10891. |
| 30 | BITIRIM C V, OZER Z B, AKCALI K C. Estrogen receptor α regulates the expression of adipogenic genes genetically and epigenetically in rat bone marrow-derived mesenchymal stem cells[J]. Peer J, 2021, 9: e12071. |
| 31 | 李凤娟, 魏苏宁, 王绿娅, 等. 雌激素抑制脂滴包被蛋白perilipin 2减少肝细胞脂质沉积[J]. 心肺血管病杂志, 2018, 37(7): 687-691. |
| 31 | LI F J, WEI S N, WANG L Y, et al. Estrogen reduces lipid deposition in liver cells by inhibiting perilipin 2[J]. Journal of Cardiovascular and Pulmonary Diseases, 2018, 37(7): 687-691. |
| 32 | TRAMUNT B, SMATI S, GRANDGEORGE N, et al. Sex differences in metabolic regulation and diabetes susceptibility[J]. Diabetologia, 2020, 63(3): 453-461. |
| 33 | IWASA T, MATSUZAKI T, MAYILA Y, et al. Oxytocin treatment reduced food intake and body fat and ameliorated obesity in ovariectomized female rats[J]. Neuropeptides, 2019, 75: 49-57. |
| 34 | MA H, SPRECHER H W, KOLATTUKUDY P E. Estrogen-induced production of a peroxisome proliferator-activated receptor (PPAR) ligand in a PPARγ-expressing tissue[J]. J Biol Chem, 1998, 273(46): 30131-30138. |
| 35 | NIRANJAN M K, KOIRI R K, SRIVASTAVA R. Expression of estrogen receptor α in response to stress and estrogen antagonist tamoxifen in the shell gland of Gallus gallus domesticus: involvement of anti-oxidant system and estrogen[J]. Stress, 2021, 24(3): 261-272. |
| 36 | BESSE-PATIN A, LéVEILLé M, OROPEZA D, et al. Estrogen signals through peroxisome proliferator-activated receptor?γ coactivator 1α to reduce oxidative damage associated with diet-induced fatty liver disease[J]. Gastroenterology, 2017, 152(1): 243-256. |
| 37 | HIGASHI T, FRIEDMAN S L, HOSHIDA Y. Hepatic stellate cells as key target in liver fibrosis[J]. Adv Drug Deliv Rev, 2017, 121: 27-42. |
| 38 | CORTES E, LACHOWSKI D, RICE A, et al. Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor[J]. Oncogene, 2019, 38(16): 2910-2922. |
| 39 | LEE Y H, SON J Y, KIM K S, et al. Estrogen deficiency potentiates thioacetamide-induced hepatic fibrosis in sprague-dawley rats[J]. Int J Mol Sci, 2019, 20(15): 3709. |
| 40 | SHIMIZU I, MIZOBUCHI Y, YASUDA M, et al. Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro[J]. Gut, 1999, 44(1): 127-136. |
| 41 | LOBO R A. Hormone-replacement therapy: current thinking[J]. Nat Rev Endocrinol, 2017, 13(4): 220-231. |
| 42 | PAPAEFTHYMIOU A, DOULBERIS M, KARAFYLLIDOU K, et al. Effect of spironolactone on pharmacological treatment of nonalcoholic fatty liver disease[J]. Minerva Endocrinol (Torino), 2021. DOI: 10. 23736/S2724-6507.21.03564-8. |
| 43 | LI H, JIA E N, HONG Y, et al. Phytoestrogens and NAFLD: possible mechanisms of action[J]. Mini Rev Med Chem, 2020, 20(7): 578-583. |
| 44 | ZAMANI-GARMSIRI F, HASHEMNIA S M R, SHABANI M, et al. Combination of metformin and genistein alleviates non-alcoholic fatty liver disease in high-fat diet-fed mice[J]. J Nutr Biochem, 2021, 87: 108505. |
| 45 | LUO Z H, LIU Z W, MAO Y, et al. Cajanolactone A, a stilbenoid from Cajanus cajan, prevents ovariectomy-induced obesity and liver steatosis in mice fed a regular diet[J]. Phytomedicine, 2020, 78: 153290. |
| 46 | CHEN Y R, QUE R Y, ZHANG N, et al. Saikosaponin-d alleviates hepatic fibrosis through regulating GPER1/autophagy signaling[J]. Mol Biol Rep, 2021, 48(12): 7853-7863. |
| 47 | LIN L B, ZHOU M G, QUE R Y, et al. Saikosaponin-d protects against liver fibrosis by regulating the estrogen receptor?β/NLRP3 inflammasome pathway[J]. Biochem Cell Biol, 2021, 99(5): 666-674. |
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