Skip to main content

Advertisement

SpringerLink
Log in

Menopausal hormone therapy in women with dyslipidemia and nonalcoholic fatty liver disease

  • Short Review Article
  • Published:
Hormones Aims and scope Submit manuscript

Abstract

The cessation of ovarian function is associated with an increase in abdominal adipose tissue, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), which may contribute to the augmented cardiovascular risk observed in postmenopausal women. After ovarian function stops, circulating triglyceride, total cholesterol, and low-density lipoprotein-cholesterol (LDL-C) concentrations increase, whereas high-density lipoprotein-cholesterol (HDL-C) and lipoprotein (Lp(a)) remain essentially unchanged. Similarly, the rates of NAFLD, possibly including the advanced forms of the disease (e.g., hepatic fibrosis), increase in postmenopausal compared with premenopausal women. These effects make menopausal hormone therapy (MHT) an attractive way to restore them. Estrogen per os decreases LDL-C and Lp(a) and increases HDL-C and triglyceride concentrations. The transdermal administration of estrogen has a more neutral effect on triglycerides, albeit a less beneficial effect on LDL-C, HDL-C, and Lp(a). Co-administration of a progestagen diminishes the effect of estrogen on LDL-C, HDL-C, and Lp(a), which, however, remains beneficial. Importantly, the effect may vary with different progestagens, being lesser with natural progesterone and dydrogesterone. Regarding the effect of MHT on NAFLD, though experimental data are currently favorable, clinical evidence is to date limited and controversial. Therefore, there is a need for specifically designed clinical trials, ideally with paired liver biopsies, to demonstrate the effect of different MHT schemes on NAFLD, which is of considerable importance, given that NAFLD is more prevalent after the cessation of ovarian function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Venetsanaki V, Polyzos SA (2019) Menopause and non-alcoholic fatty liver disease: a review focusing on therapeutic perspectives. Curr Vasc Pharmacol 17:546–555

    Article  CAS  PubMed  Google Scholar 

  2. Anagnostis P, Paschou SA, Katsiki N, Krikidis D, Lambrinoudaki I, Goulis DG (2019) Menopausal Hormone Therapy and Cardiovascular Risk: Where are we Now? Curr Vasc Pharmacol 17:564–572

    Article  CAS  PubMed  Google Scholar 

  3. Polyzos SA, Kechagias S, Tsochatzis E (2021) Review article: non-alcoholic fatty liver disease and cardiovascular diseases - associations and treatment considerations. Aliment Pharmacol Ther 54:1013–1055

    Article  PubMed  Google Scholar 

  4. Perakakis N, Polyzos SA, Yazdani A, Sala-Vila A, Kountouras J, Anastasilakis AD, Mantzoros CS (2019) Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: a proof of concept study. Metab 101:154005

    Article  CAS  Google Scholar 

  5. Ambikairajah A, Walsh E, Cherbuin N (2019) Lipid profile differences during menopause: a review with meta-analysis. Menopause 26:1327–1333

    Article  PubMed  Google Scholar 

  6. Marston NA, Giugliano RP, Melloni GEM, Park JG, Morrill V, Blazing MA, Ference B, Stein E, Stroes ES, Braunwald E, Ellinor PT, Lubitz SA, Ruff CT, Sabatine MS (2022) Association of apolipoprotein B-containing lipoproteins and risk of myocardial infarction in individuals with and without atherosclerosis: distinguishing between particle concentration, type, and content. JAMA Cardiol 7:250–256

  7. Anagnostis P, Stevenson JC, Crook D, Johnston DG, Godsland IF (2016) Effects of gender, age and menopausal status on serum apolipoprotein concentrations. Clin Endocrinol (Oxf) 85:733–740

    Article  CAS  Google Scholar 

  8. Derby CA, Crawford SL, Pasternak RC, Sowers M, Sternfeld B, Matthews KA (2009) Lipid changes during the menopause transition in relation to age and weight: the Study of Women’s Health Across the Nation. Am J Epidemiol 169:1352–1361

    Article  PubMed  PubMed Central  Google Scholar 

  9. Woodard GA, Brooks MM, Barinas-Mitchell E, Mackey RH, Matthews KA, Sutton-Tyrrell K (2011) Lipids, menopause, and early atherosclerosis in Study of Women’s Health Across the Nation Heart women. Menopause 18:376–384

    Article  PubMed  PubMed Central  Google Scholar 

  10. Matthews KA, Chen X, Barinas-Mitchell E, Brooks MM, Derby CA, Harlow S, Jackson EA, Thurston RC, El Khoudary SR (2021) Age at menopause in relationship to lipid changes and subclinical carotid disease across 20 years: study of women’s health across the nation. J Am Heart Assoc 10:e021362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. de Boer LM, Oorthuys AOJ, Wiegman A, Langendam MW, Kroon J, Spijker R, Zwinderman AH, Hutten BA (2021) Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis. Eur J Prev Cardiol. https://doi.org/10.1093/eurjpc/zwab171

    Article  PubMed  Google Scholar 

  12. Makri E, Goulas A, Polyzos SA (2021) Epidemiology, pathogenesis, diagnosis and emerging treatment of nonalcoholic fatty liver disease. Arch Med Res 52:25–37

    Article  CAS  PubMed  Google Scholar 

  13. Polyzos SA, Mantzoros CS (2016) Nonalcoholic fatty future disease. Metab 65:1007–1016

    Article  CAS  Google Scholar 

  14. Polyzos SA, Kountouras J, Mantzoros CS (2019) Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metab 92:82–97

    Article  CAS  Google Scholar 

  15. Younossi ZM, Corey KE, Lim JK (2021) AGA clinical practice update on lifestyle modification using diet and exercise to achieve weight loss in the management of nonalcoholic fatty liver disease: expert review. Gastroenterology 160:912–918

    Article  PubMed  Google Scholar 

  16. Athyros VG, Alexandrides TK, Bilianou H, Cholongitas E, Doumas M, Ganotakis ES, Goudevenos J, Elisaf MS, Germanidis G, Giouleme O, Karagiannis A, Karvounis C, Katsiki N, Kotsis V, Kountouras J, Liberopoulos E, Pitsavos C, Polyzos S, Rallidis LS, Richter D, Tsapas AG, Tselepis AD, Tsioufis K, Tziomalos K, Tzotzas T, Vasiliadis TG, Vlachopoulos C, Mikhailidis DP, Mantzoros C (2017) 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 Metab 71:17–32

    CAS  Google Scholar 

  17. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, Zelber-Sagi S, Wai-Sun Wong V, Dufour JF, Schattenberg JM, Kawaguchi T, Arrese M, Valenti L, Shiha G, Tiribelli C, Yki-Järvinen H, Fan JG, Grønbæk H, Yilmaz Y, Cortez-Pinto H, Oliveira CP, Bedossa P, Adams LA, Zheng MH, Fouad Y, Chan WK, Mendez-Sanchez N, Ahn SH, Castera L, Bugianesi E, Ratziu V, George J (2020) A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol 73:202–209

    Article  PubMed  Google Scholar 

  18. Polyzos SA, Kang ES, Tsochatzis EA, Kechagias S, Ekstedt M, Xanthakos S, Lonardo A, Mantovani A, Tilg H, Côté I, Grefhorst A, Greene MW, Araujo-Vilar D, Alisi A, Casanueva F, Mantzoros CS (2020) Commentary: nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name. Metab 113:154413

    Article  CAS  Google Scholar 

  19. Gutierrez-Grobe Y, Ponciano-Rodriguez G, Ramos MH, Uribe M, Mendez-Sanchez N (2010) Prevalence of non alcoholic fatty liver disease in premenopausal, posmenopausal and polycystic ovary syndrome women. The role of estrogens Ann Hepatol 9:402–409

    Article  PubMed  Google Scholar 

  20. Völzke H, Schwarz S, Baumeister SE, Wallaschofski H, Schwahn C, Grabe HJ, Kohlmann T, John U, Dören M (2007) Menopausal status and hepatic steatosis in a general female population. Gut 56:594–595

    Article  PubMed  PubMed Central  Google Scholar 

  21. DiStefano JK (2020) NAFLD and NASH in postmenopausal women: implications for diagnosis and treatment. Endocrinol 161:bqaa134

    Article  Google Scholar 

  22. Yang JD, Abdelmalek MF, Pang H, Guy CD, Smith AD, Diehl AM, Suzuki A (2014) Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatol 59:1406–1414

    Article  CAS  Google Scholar 

  23. Yoneda M, Thomas E, Sumida Y, Eguchi Y, Schiff ER (2014) The influence of menopause on the development of hepatic fibrosis in nonobese women with nonalcoholic fatty liver disease. Hepatol 60:1792

    Article  Google Scholar 

  24. Polyzos SA, Kountouras J, Zavos C, Deretzi G (2012) Nonalcoholic fatty liver disease: Multimodal treatment options for a pathogenetically multiple-hit disease. J Clin Gastroenterol 46:272–284

    Article  PubMed  Google Scholar 

  25. Klair JS, Yang JD, Abdelmalek MF, Guy CD, Gill RM, Yates K, Unalp-Arida A, Lavine JE, Clark JM, Diehl AM, Suzuki A (2016) A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatol 64:85–91

    Article  CAS  Google Scholar 

  26. Polyzos SA, Kountouras J, Tsatsoulis A, Zafeiriadou E, Katsiki E, Patsiaoura K, Zavos C, Anastasiadou VV, Slavakis A (2013) Sex steroids and sex hormone-binding globulin in postmenopausal women with nonalcoholic fatty liver disease. Horm (Athens) 12:405–416

    Article  Google Scholar 

  27. Polyzos SA, Kountouras J, Mantzoros CS (2017) Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol 42:92–108

    PubMed  Google Scholar 

  28. Godsland IF (2001) Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974–2000. Fertil Steril 75:898–915

    Article  CAS  PubMed  Google Scholar 

  29. L’Hermite M, Simoncini T, Fuller S, Genazzani AR (2008) Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas 60:185–201

    Article  PubMed  CAS  Google Scholar 

  30. Kotecha PT, Godsland IF, Crook D, Stevenson JC (2020) Effects of tibolone or continuous combined oestradiol and norethisterone acetate on lipids, high-density lipoprotein subfractions and apolipoproteins in postmenopausal women in a two-year, randomized, double-blind, placebo-controlled trial. Clin Endocrinol (Oxf) 92:303–311

    Article  CAS  Google Scholar 

  31. Christodoulakos GE, Lambrinoudaki IV, Panoulis CP, Papadias CA, Kouskouni EE, Creatsas GC (2004) Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women. Gynecol Endocrinol 18:244–257

    Article  CAS  PubMed  Google Scholar 

  32. Anagnostis P, Galanis P, Chatzistergiou V, Stevenson JC, Godsland IF, Lambrinoudaki I, Theodorou M, Goulis DG (2017) The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: a systematic review and meta-analysis. Maturitas 99:27–36

    Article  CAS  PubMed  Google Scholar 

  33. Miller VT, LaRosa J, Barnabei V, Kessler C, Levin G, Smith-Roth A, Grifin M (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 273:199–208

    Article  Google Scholar 

  34. Anagnostis P, Bitzer J, Cano A, Ceausu I, Chedraui P, Durmusoglu F, Erkkola R, Goulis DG, Hirschberg AL, Kiesel L, Lopes P, Pines A, van Trotsenburg M, Lambrinoudaki I, Rees M (2020) Menopause symptom management in women with dyslipidemias: an EMAS clinical guide. Maturitas 135:82–88

    Article  CAS  PubMed  Google Scholar 

  35. Yang F, Li N, Gaman MA, Wang N (2021) Raloxifene has favorable effects on the lipid profile in women explaining its beneficial effect on cardiovascular risk: a meta-analysis of randomized controlled trials. Pharmacol Res 166:105512

    Article  CAS  PubMed  Google Scholar 

  36. Kotani K, Sahebkar A, Serban C, Andrica F, Toth PP, Jones SR, Kostner K, Blaha MJ, Martin S, Rysz J, Glasser S, Ray KK, Watts GF, Mikhailidis DP, Banach M (2015) Tibolone decreases Lipoprotein(a) levels in postmenopausal women: a systematic review and meta-analysis of 12 studies with 1009 patients. Atheroscler 242:87–96

    Article  CAS  Google Scholar 

  37. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Muñoz D, Smith SC Jr, Virani SS, Williams KA Sr, Yeboah J, Ziaeian B (2019) 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 74:e177–e232

    Article  PubMed  PubMed Central  Google Scholar 

  38. Darling GM, Johns JA, McCloud PI, Davis SR (1997) Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women. N Engl J Med 337:595–601

    Article  CAS  PubMed  Google Scholar 

  39. Davidson MH, Testolin LM, Maki KC, von Duvillard S, Drennan KB (1997) A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women. Arch Intern Med 157:1186–1192

    Article  CAS  PubMed  Google Scholar 

  40. Lee C, Kim J, Jung Y (2019) Potential therapeutic application of estrogen in gender disparity of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Cells 8:1259

    Article  CAS  PubMed Central  Google Scholar 

  41. McKenzie J, Fisher BM, Jaap AJ, Stanley A, Paterson K, Sattar N (2006) Effects of HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo-controlled trial. Clin Endocrinol (Oxf) 65:40–44

    Article  CAS  Google Scholar 

  42. Florentino GS, Cotrim HP, Vilar CP, Florentino AV, Guimarães GM, Barreto VS (2013) Nonalcoholic fatty liver disease in menopausal women. Arq Gastroenterol 50:180–185

    Article  PubMed  Google Scholar 

  43. Wang J, Wu AH, Stanczyk FZ, Porcel J, Noureddin M, Terrault NA, Wilkens LR, Setiawan VW (2021) Associations between reproductive and hormone-related factors and risk of nonalcoholic fatty liver disease in a multiethnic population. Clin Gastroenterol Hepatol 19:1258–1266

    Article  CAS  PubMed  Google Scholar 

  44. Yang JD, Abdelmalek MF, Guy CD, Gill RM, Lavine JE, Yates K, Klair J, Terrault NA, Clark JM, Unalp-Arida A, Diehl AM, Suzuki A (2017) Patient sex, reproductive status, and synthetic hormone use associate with histologic severity of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 15:127–131

    Article  CAS  PubMed  Google Scholar 

  45. Jarvis H, Craig D, Barker R, Spiers G, Stow D, Anstee QM, Hanratty B (2020) Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of population-based observational studies. PLoS Med 17:e1003100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Polyzos SA, Kang ES, Boutari C, Rhee EJ, Mantzoros CS (2020) Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. Metab 111S:154203

    Article  CAS  Google Scholar 

  47. Doulberis M, Papadimitriou K, Papaefthymiou A, Kountouras J, Polyzos SA (2020) The therapeutic potential of C-C chemokine receptor antagonists in nonalcoholic steatohepatitis. Explor Med 1:170–183

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Stergios A. Polyzos

  2. Menopause Unit, 2nd Department of Obstetrics and Gynecology, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

    Irene Lambrinoudaki

  3. Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Dimitrios G. Goulis

Authors
  1. Stergios A. Polyzos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irene Lambrinoudaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dimitrios G. Goulis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SAP: conception and design of the study, review of the literature, acquisition of articles, interpretation of articles, drafting of the article, critical revision of the article for important intellectual content, and final approval of the version to be submitted.

IL: interpretation of articles, critical revision of the article for important intellectual content, and final approval of the version to be submitted.

DGG: interpretation of articles, critical revision of the article for important intellectual content, and final approval of the version to be submitted.

All authors ensure that the article is original work, has not been previously published, and is not under consideration for publication elsewhere.

Corresponding author

Correspondence to Stergios A. Polyzos.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Polyzos, S.A., Lambrinoudaki, I. & Goulis, D.G. Menopausal hormone therapy in women with dyslipidemia and nonalcoholic fatty liver disease. Hormones 21, 375–381 (2022). https://doi.org/10.1007/s42000-022-00369-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42000-022-00369-8

Keywords

Search

Navigation