The Impact of Menopausal Hormone Therapy on Liver and Biliary Tract Health
https://doi.org/10.22416/1382-4376-2025-35-3-104-113
Abstract
Aim: to provide summarized data on the relationship between menopausal hormone therapy (MHT) and liver health.
Key points. A decrease in estrogen production during the menopausal transition and a deficiency of estrogen and progesterone during postmenopause significantly affect lipid and carbohydrate metabolism and can lead to impaired liver function. With age, the risk of developing metabolic-associated fatty liver disease (MAFLD) in women increases significantly, due to a combination of hormonal changes, a higher incidence of metabolic disorders, and age-related factors. In turn, MAFLD is associated with an increased risk of cardiovascular disease, diabetes mellitus and metabolic disorders. In the absence of well-timed hormonal support, postmenopausal women are at high risk of developing serious complications, therefore, it is extremely important to select MHT with a favorable efficacy and safety profile. The approach to prescribing MHT should take into account the patient’s medical history, individual characteristics, as well as the mode of drug administration, considering the minimum effective dose.
Conclusion. Oral combination MHT provides positive metabolic effects through the first-pass metabolism but is not associated with additional health risks.
About the Authors
A. O. Bueverov
Moscow Regional Research Clinical Institute named after M.F. Vladimirsky (MONIKI)
Russian Federation
Russian Federation
Alexey O. Bueverov — Dr. Sci. (Med.), Professor, Leading Researcher at the Department of Hepatology
129110, Moscow, Shchepkina str., 61/2
N. I. Tapilskaya
Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott;
Saint Petersburg State Pediatric Medical University
Russian Federation
Russian Federation
Natalia I. Tapilskaya — Dr. Sci. (Med.), Professor, Head of the Department of Reproductive Technologies; Professor of the Department of Obstetrics and Gynecology
194100, Saint Petersburg, Litovskaya str., 2
References
1. Devarbhavi H., Asrani S.K., Arab J.P., Nartey Y.A., Pose E., Kamath P.S. Global burden of liver disease: 2023 update. J Hepatol. 2023;79(2):516–37. DOI: 10.1016/j.jhep.2023.03.017
2. Georgieva M., Xenodochidis C., Krasteva N. Old age as a risk factor for liver diseases: Modern therapeutic approaches. Exp Gerontol. 2023;184:112334. DOI: 10.1016/j.exger.2023.112334
3. Wang X., Yu W., Jiang G., Li H., Li S., Xie L., et al. Global epidemiology of gallstones in the 21st century: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2024;22(8):1586–95. DOI: 10.1016/j.cgh.2024.01.051
4. Komova A., Maevskaya M., Ivashkin V. Prevalence of liver disease in Russia’s largest city: A population-based study. Am J Clin Med Res. 2014;2(5):99–102. DOI: 10.12691/ajcmr-2-5-2
5. Желчнокаменная болезнь. Клинические рекомендации. 2024. [Gallstone Disease. Clinical Guidelines. 2024. (In Russ.)]. URL: https://cr.minzdrav.gov.ru/viewcr/877_1
6. Panay N., Ang S.B., Cheshire R., Goldstein S.R., Maki P., Nappi R.E.; International Menopause Society Board. Menopause and MHT in 2024: Addressing the key controversies — an International Menopause Society White Paper. Climacteric. 2024;27(5):441–57. DOI: 10.1080/13697137.2024.2394950
7. Menopause and female climacteric states. Clinical Guidelines. 2021. (In Russ.). URL: https://cr.minzdrav.gov.ru/view-cr/117_2
8. Della Torre S. Non-alcoholic fatty liver disease as a canonical example of metabolic inflammatory-based liver disease showing a sex-specific prevalence: Relevance of estrogen signaling. Front Endocrinol (Lausanne). 2020;11:572490. DOI: 10.3389/fendo.2020.572490
9. Xu L., Yuan Y., Che Z., Tan X., Wu B., Wang C., et al. The hepatoprotective and hepatotoxic roles of sex and sex-related hormones. Front Immunol. 2022;13:939631. DOI: 10.3389/fimmu.2022.939631
10. Robeva R., Mladenović D., Vesković M., Hrnčić D., Bjekić-Macut J., Stanojlović O., et al. The interplay between metabolic dysregulations and non-alcoholic fatty liver disease in women after menopause. Maturitas. 2021;151:22–30. DOI: 10.1016/j.maturitas.2021.06.012
11. Batmunkh B., Choijookhuu N., Srisowanna N., Byambatsogt U., Synn Oo P., Noor Ali M., et al. Estrogen accelerates cell proliferation through estrogen receptor α during rat liver regeneration after partial hepatectomy. Acta Histochem Cytochem. 2017;50(1):39–48. DOI: 10.1267/ahc.17003
12. Chaturantabut S., Shwartz A., Evason K.J., Cox A.G., Labella K., Schepers A.G., et al. Estrogen activation of G-protein-coupled estrogen receptor 1 regulates phosphoinositide 3-kinase and mTOR signaling to promote liver growth in zebrafish and proliferation of human hepatocytes. Gastroenterology. 2019;156(6):1788–804.e13. DOI: 10.1053/j.gastro.2019.01.010
13. Galmés-Pascual B.M., Nadal-Casellas A., Bauza-Thorbrügge M., Sbert-Roig M., García-Palmer F.J., Proenza A.M., et al. 17β-estradiol improves hepatic mitochondrial biogenesis and function through PGC1B. J Endocrinol. 2017;232(2):297–308. DOI: 10.1530/JOE-16-0350
14. Yang W., Lu Y., Xu Y., Xu L., Zheng W., Wu Y., et al. Estrogen represses hepatocellular carcinoma (HCC) growth via inhibiting alternative activation of tumor-associated macrophages (TAMs). J Biol Chem. 2012;287(48):40140–9. DOI: 10.1074/jbc.M112.348763
15. Naugler W.E., Sakurai T., Kim S., Maeda S., Kim K., Elsharkawy A.M., et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–4. DOI: 10.1126/science.1140485
16. Winn N.C., Jurrissen T.J., Grunewald Z.I., Cunningham R.P., Woodford M.L., Kanaley J.A., et al. Estrogen receptor-α signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver. Am J Physiol Endocrinol Metab. 2019;316(2):E156–67. DOI: 10.1152/ajpendo.00259.2018
17. Ivashkin V.T., Drapkina O.M., Maevskaya M.V., Raikhelson K.L., Okovityi S.V., Zharkova M.S., et al. Clinical guidelines of the Russian Society for the Study of the Liver, Russian Gastroenterological Association, Russian Society for the Prevention of Non-Communicable Diseases, Russian Association of Endocrinologists, Russian Scientific Medical Society of Therapists, National Society of Preventive Cardiology, Russian Association of Gerontologists and Geriatricians on non-alcoholic fatty liver disease. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2025;35(1):94–152. (In Russ.). DOI: 10.22416/1382-4376-2025-35-1-94-152
18. Daher D., Dahan K.S.E., Singal A.G. Non-alcoholic fatty liver disease-related hepatocellular carcinoma. J Liver Cancer. 2023;23(1):127–42. DOI: 10.17998/jlc.2022.12.30
19. Li B., Zhang C., Zhan Y.T. Nonalcoholic fatty liver disease cirrhosis: A review of its epidemiology, risk factors, clinical presentation, diagnosis, management, and prognosis. Can J Gastroenterol Hepatol. 2018;2018:2784537. DOI: 10.1155/2018/2784537
20. Younossi Z.M., Golabi P., Paik J.M., Henry A., Van Dongen C., Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review. Hepatology. 2023;77(4):1335–47. DOI: 10.1097/HEP.0000000000000004
21. Le M.H., Yeo Y.H., Zou B., Barnet S., Henry L., Cheung R., et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. Clin Mol Hepatol. 2022;28(4):841–50. DOI: 10.3350/cmh.2022.0239
22. Powell E.E., Wong V.W.S., Rinella M. Non-alcoholic fatty liver disease. Lancet. 2021;397(10290):2212–24. DOI: 10.1016/S0140-6736(20)32511-3
23. Han S.K., Baik S.K., Kim M.Y. Non-alcoholic fatty liver disease: Definition and subtypes. Clin Mol Hepatol. 2023;29(Suppl):S5–16. DOI: 10.3350/cmh.2022.0424
24. Quek J., Chan K.E., Wong Z.Y., Tan C., Tan B., Lim W.H., et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: A systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(1):20–30. DOI: 10.1016/S2468-1253(22)00317-X
25. Younossi Z.M., Golabi P., de Avila L., Paik J.M., Srishord M., Fukui N., et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801. DOI: 10.1016/j.jhep.2019.06.021
26. Eslam M., Newsome P.N., Sarin S.K., Anstee Q.M., Targher G., Romero-Gomez M., et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73(1):202–9. DOI: 10.1016/j.jhep.2020.03.039
27. Eslam M., Sanyal A.J., George J.; International Consensus Panel. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158(7):1999–2014.e1. DOI: 10.1053/j.gastro.2019.11.312
28. Caligiuri A., Gentilini A., Marra F. Molecular pathogenesis of NASH. Int J Mol Sci. 2016;17(9):1575. DOI: 10.3390/ijms17091575
29. Green C.J., Hodson L. The influence of dietary fat on liver fat accumulation. Nutrients. 2014;6(11):5018–33. DOI: 10.3390/nu6115018
30. Ferramosca A., Zara V. Modulation of hepatic steatosis by dietary fatty acids. World J Gastroenterol. 2014;20(7):1746–55. DOI: 10.3748/wjg.v20.i7.1746
31. Wang W., Zhu J., Lyu F., Panigrahy D., Ferrara K.W., Hammock B., et al. ω-3 polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer. Prostaglandins Other Lipid Mediat. 2014;113–115:13–20. DOI: 10.1016/j.prostaglandins.2014.07.002
32. Byrne C.D. Ectopic fat, insulin resistance and non-alcoholic fatty liver disease. Proc Nutr Soc. 2013;72(4):412–9. DOI: 10.1017/S0029665113001249
33. Maevskaya M.V., Kotovskaya Yu.V., Ivashkin V.T., Tkacheva O.N., Troshina E.A., Shestakova M.V., et al. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. Terapevticheskii Arkhiv. 2022;94(2):216–53. (In Russ.). DOI: 10.26442/00403660.2022.02.201363
34. Bessone F., Razori M.V., Roma M.G. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci. 2019;76(1):99–128. DOI: 10.1007/s00018-018-2947-0
35. Lonardo A., Nascimbeni F., Ballestri S., Fairweather D., Win S., Than T.A., et al. Sex differences in nonalcoholic fatty liver disease: State of the art and identification of research gaps. Hepatology. 2019;70(4):1457–69. DOI: 10.1002/hep.30626
36. Eng P.C., Forlano R., Tan T., Manousou P., Dhillo W.S., Izzi-Engbeaya C. Non-alcoholic fatty liver disease in women — current knowledge and emerging concepts. JHEP Rep. 2023;5(10):100835. DOI: 10.1016/j.jhepr.2023.100835
37. DiStefano J.K. NAFLD and NASH in postmenopausal women: Implications for diagnosis and treatment. Endocrinology. 2020;161(10):bqaa134. DOI: 10.1210/endocr/bqaa134
38. Kozakowski J., Gietka-Czernel M., Leszczyńska D., Majos A. Obesity in menopause — our negligence or an unfortunate inevitability? Prz Menopauzalny. 2017;16(2):61–5. DOI: 10.5114/pm.2017.68594
39. Opoku A.A., Abushama M., Konje J.C. Obesity and menopause. Best Pract Res Clin Obstet Gynaecol. 2023;88:102348. DOI: 10.1016/j.bpobgyn.2023.102348
40. Fabbrini E., Sullivan S., Klein S. Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Hepatology. 2010;51(2):679–89. DOI: 10.1002/hep.23280
41. Lee H.H., Lee H.A., Kim E.J., Kim H.Y., Kim H.C., Ahn S.H., et al. Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease. Gut. 2024;73(3):533–40. DOI: 10.1136/gutjnl-2023-331003
42. Moon J.H., Jeong S., Jang H., Koo B.K., Kim W. Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: A nationwide cohort study. EClinicalMedicine. 2023;65:102292. DOI: 10.1016/j.eclinm.2023.102292
43. Zheng H., Sechi L.A., Navarese E.P., Casu G., Vidili G. Metabolic dysfunction-associated steatotic liver disease and cardiovascular risk: A comprehensive review. Cardiovasc Diabetol. 2024;23(1):346. DOI: 10.1186/s12933-024-02434-5
44. Shang Y., Nasr P., Widman L., Hagström H. Risk of cardiovascular disease and loss in life expectancy in NAFLD. Hepatology. 2022;76(5):1495–505. DOI: 10.1002/hep.32519
45. Stinton L.M., Myers R.P., Shaffer E.A. Epidemiology of gallstones. Gastroenterol Clin North Am. 2010;39(2):157–69. DOI: 10.1016/j.gtc.2010.02.003
46. Cirillo D.J. Effect of estrogen therapy on gallbladder disease. JAMA. 2005;293(3):330–9. DOI: 10.1001/jama.293.3.330
47. Wang H.H., Liu M., Clegg D.J., Portincasa P., Wang D.Q. New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. Biochim Biophys Acta. 2009;1791(11):1037–47. DOI: 10.1016/j.bbalip.2009.06.006
48. Goldštajn M.Š., Mikuš M., Ferrari F.A., Bosco M., Uccella S., Noventa M., et al. Effects of transdermal versus oral hormone replacement therapy in postmenopause: A systematic review. Arch Gynecol Obstet. 2023;307(6):1727–45. DOI: 10.1007/s00404-022-06647-5
49. Polyzos S.A., Lambrinoudaki I., Goulis D.G. Menopausal hormone therapy in women with dyslipidemia and nonalcoholic fatty liver disease. Hormones (Athens). 2022;21(3):375–81. DOI: 10.1007/s42000-022-00369-8
50. Kim S.E., Min J.S., Lee S., Lee D.Y., Choi D. Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration. Sci Rep. 2023;13(1):15461. DOI: 10.1038/s41598-023-42788-6
51. Speksnijder E.M., Ten Noever de Brauw G.V., Malekzadeh A., Bisschop P.H., Stenvers D.J., Siegelaar S.E. Effect of postmenopausal hormone therapy on glucose regulation in women with type 1 or type 2 diabetes: A systematic review and meta-analysis. Diabetes Care. 2023;46(10):1866–75. DOI: 10.2337/dc23-0451
52. Manson J.E., Aragaki A.K., Rossouw J.E., Anderson G.L., Prentice R.L., LaCroix A.Z., et al.; WHI Investigators. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative randomized trials. JAMA. 2017;318(10):927–38. DOI: 10.1001/jama.2017.11217
53. Manson J.E., Chlebowski R.T., Stefanick M.L., Aragaki A.K., Rossouw J.E., Prentice R.L., 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):1353–68. DOI: 10.1001/jama.2013.278040
54. Liu B., Beral V., Balkwill A., Green J., Sweetland S., Reeves G.; Million Women Study Collaborators. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ. 2008;337:a386. DOI: 10.1136/bmj.a386
55. Yuk J.S., Park J.Y. Menopausal hormone therapy increases the risk of gallstones: Health Insurance Database in South Korea (HISK)-based cohort study. PLoS One. 2023;18(12):e0294356. DOI: 10.1371/journal.pone.0294356
56. Ren M., Yu Q., Custodio M.G., Simoncini T., Nappi R.E., Tatarchuk T., et al. Low-dose and ultra-low-dose estradiol and dydrogesterone in postmenopause: An analysis by body mass index. Climacteric. 2025;28(1):21–7. DOI: 10.1080/13697137.2024.2418497
57. Tatarchuk T., Stevenson J.C., Yu Q., Kahler E., Graziano Custodio M., Ren M., et al. Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis. Gynecol Endocrinol. 2024;40(1):2375577. DOI: 10.1080/0951359.2024.2375577
58. Stevenson J.C., Ren M., Kahler E., Custodio M.G., Nappi R.E., Tatarchuk T., et al. Ultra-low dose estradiol and dydrogesterone for the treatment of menopausal symptoms in a pooled, multi-ethnic population. Maturitas. 2024;190:108117. DOI: 10.1016/j.maturitas.2024.108117
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Bueverov A.O., Tapilskaya N.I. The Impact of Menopausal Hormone Therapy on Liver and Biliary Tract Health. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2025;35(3):104-113. https://doi.org/10.22416/1382-4376-2025-35-3-104-113
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