Advertisement

Current Hepatology Reports

, Volume 18, Issue 4, pp 425–432 | Cite as

NAFLD in Women: Unique Pathways, Biomarkers, and Therapeutic Opportunities

  • Liyun Yuan
  • Ani Kardashian
  • Monika SarkarEmail author
Fatty Liver Disease (V Ajmera, Section Editor)
  • 23 Downloads
Part of the following topical collections:
  1. Topical Collection on Fatty Liver Disease

Abstract

Purpose of review

In this review article, we evaluate sex differences in the natural history of NAFLD and highlight distinct risk profiles of women with NAFLD, as well as unique treatment considerations and research gaps.

Summary of Findings

Reproductive factors, such as menopausal status, should be considered when evaluating NAFLD risk in women, as well as additional reproductive risk factors such as age at menarche, presence of polycystic ovary syndrome, and gestational diabetes. Women do appear to have lower risk for hepatocellular carcinoma from NASH, as well as lower mortality from NASH cirrhosis than men, although among women, NASH is now the leading indication for liver transplant. Data on sex differences in biomarker development and clinical trials are lacking, and researchers should be encouraged to evaluate biomarker performance by sex, and specifically report clinical trial endpoints in women.

Keywords

Nonalcoholic fatty liver Hormones Sex differences Women 

Notes

Compliance with Ethical Standards

Conflict of Interest

Liyun Yuan and Ani Kardashian each declare no potential conflicts of interest.

Monika Sarkar is a site PI for a pharmaceutical sponsored drug trial in women with NAFLD and PCOS for Zydus Pharmaceuticals.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Younossi Z, Stepanova M, Ong JP, et al. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin Gastroenterol Hepatol : Off Clin Pract J Am Gastroenterol Assoc. 2018.Google Scholar
  3. 3.
    Noureddin M, Vipani A, Bresee C, et al. NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances. Am J Gastroenterol. 2018;113(11):1649–59.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Lonardo A, Nascimbeni F, Ballestri S, et al. Sex differences in NAFLD: state of the art and identification of Research Gaps. Hepatology. 2019.Google Scholar
  5. 5.
    Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40(6):1387–95.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Wong VW, Chu WC, Wong GL, et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. Gut. 2012;61(3):409–15.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Zhou YJ, Li YY, Nie YQ, et al. Prevalence of fatty liver disease and its risk factors in the population of South China. World J Gastroenterol: WJG. 2007;13(47):6419–24.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Wang Z, Xu M, Hu Z, Hultstrom M, Lai E. Sex-specific prevalence of fatty liver disease and associated metabolic factors in Wuhan, south central China. Eur J Gastroenterol Hepatol. 2014;26(9):1015–21.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Zelber-Sagi S, Lotan R, Shlomai A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol. 2012;56(5):1145–51.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Wong VW, Wong GL, Yeung DK, et al. Incidence of non-alcoholic fatty liver disease in Hong Kong: a population study with paired proton-magnetic resonance spectroscopy. J Hepatol. 2015;62(1):182–9.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Sung KC, Kim BS, Cho YK, et al. Predicting incident fatty liver using simple cardio-metabolic risk factors at baseline. BMC Gastroenterol. 2012;12:84.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Xu C, Yu C, Ma H, Xu L, Miao M, Li Y. Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study. Am J Gastroenterol. 2013;108(8):1299–304.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Allen AM, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year-community study. Hepatology. 2018;67(5):1726–36.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Long MT, Pedley A, Massaro JM, et al. A simple clinical model predicts incident hepatic steatosis in a community-based cohort: the Framingham Heart Study. Liver Int: Off J Int Assoc Stud Liver. 2018;38(8):1495–503.CrossRefGoogle Scholar
  15. 15.
    Hamaguchi M, Kojima T, Ohbora A, Takeda N, Fukui M, Kato T. Aging is a risk factor of nonalcoholic fatty liver disease in premenopausal women. World J Gastroenterol: WJG. 2012;18(3):237–43.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Tapper EB, Krajewski K, Lai M, et al. Simple non-invasive biomarkers of advanced fibrosis in the evaluation of non-alcoholic fatty liver disease. Gastroenterol Rep (Oxf). 2014;2(4):276–80.CrossRefGoogle Scholar
  17. 17.
    Bambha K, Belt P, Abraham M, et al. Ethnicity and nonalcoholic fatty liver disease. Hepatology. 2012;55(3):769–80.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Turola E, Petta S, Vanni E, et al. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis. Dis Model Mech. 2015;8(9):1037–46.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Singh DK, Sakhuja P, Malhotra V, Gondal R, Sarin SK. Independent predictors of steatohepatitis and fibrosis in Asian Indian patients with non-alcoholic steatohepatitis. Dig Dis Sci. 2008;53(7):1967–76.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Hossain N, Afendy A, Stepanova M, et al. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol : Off Clin Pract J Am Gastroenterol Assoc. 2009;7(11):1224–9 1229 e1221-1222.CrossRefGoogle Scholar
  21. 21.
    Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51(2):371–9.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Neuschwander-Tetri BA, Clark JM, Bass NM, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52(3):913–24.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology. 2018;155(2):443–57 e417.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972–8.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Yasui K, Hashimoto E, Komorizono Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc. 2011;9(5):428–33 quiz e450.CrossRefGoogle Scholar
  27. 27.
    Yang D, Hanna DL, Usher J, et al. Impact of sex on the survival of patients with hepatocellular carcinoma: a Surveillance, Epidemiology, and End Results analysis. Cancer. 2014;120(23):3707–16.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Wu EM, Wong LL, Hernandez BY, et al. Gender differences in hepatocellular cancer: disparities in nonalcoholic fatty liver disease/steatohepatitis and liver transplantation. Hepatoma Res. 2018;4.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Narayanan P, Mara K, Izzy M, et al. Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation. Transplantation. 2019;103(1):e14–21.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Gitto S, de Maria N, di Benedetto F, et al. De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients. Eur J Gastroenterol Hepatol. 2018;30(7):766–73.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    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 Pt 1):138–43.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Florentino GS, Cotrim HP, Vilar CP, Florentino AV, Guimaraes GM, Barreto VS. Nonalcoholic fatty liver disease in menopausal women. Arq Gastroenterol. 2013;50(3):180–5.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Volzke H, Schwarz S, Baumeister SE, et al. Menopausal status and hepatic steatosis in a general female population. Gut. 2007;56(4):594–5.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes. 2008;32(6):949–58.CrossRefGoogle Scholar
  35. 35.
    Florio AA, Graubard BI, Yang B, et al. Oophorectomy and risk of non-alcoholic fatty liver disease and primary liver cancer in the Clinical Practice Research Datalink. Eur J Epidemiol. 2019.Google Scholar
  36. 36.
    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.Google Scholar
  37. 37.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Suzuki A, Abdelmalek MF, Unalp-Arida A, et al. Regional anthropometric measures and hepatic fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol:Off Clin Pract J Am Gastroenterol Assoc. 2010;8(12):1062–9.CrossRefGoogle Scholar
  41. 41.
    Chen VL, Wright AP, Halligan B, et al. Body composition and genetic lipodystrophy risk score associate with nonalcoholic fatty liver disease and liver fibrosis. Hepatol Commun. 2019;3(8):1073–84.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Su X, Xu J, Zheng C. The relationship between non-alcoholic fatty liver and skeletal muscle mass to visceral fat area ratio in women with type 2 diabetes. BMC Endocr Disord. 2019;19(1):76.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kaplowitz PB. Link between body fat and the timing of puberty. Pediatrics. 2008;121(Suppl 3):S208–17.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Lee JM, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH, Lumeng JC. Weight status in young girls and the onset of puberty. Pediatrics. 2007;119(3):e624–30.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Davison KK, Susman EJ, Birch LL. Percent body fat at age 5 predicts earlier pubertal development among girls at age 9. Pediatrics. 2003;111(4 Pt 1):815–21.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. J Clin Endocrinol Metab. 1997;82(9):2849–55.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Ryu S, Chang Y, Choi Y, et al. Age at menarche and non-alcoholic fatty liver disease. J Hepatol. 2015;62(5):1164–70.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Yi KH, Hwang JS, Lim SW, Lee JA, Kim DH, Lim JS. Early menarche is associated with non-alcoholic fatty liver disease in adulthood. Pediatr Int. 2017;59(12):1270–5.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    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. 2015;23(2):468–74.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57.CrossRefGoogle Scholar
  51. 51.
    Rocha ALL, Faria LC, Guimaraes TCM, et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J Endocrinol Investig. 2017;40(12):1279–88.CrossRefGoogle Scholar
  52. 52.
    Cerda C, Perez-Ayuso RM, Riquelme A, et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol. 2007;47(3):412–7.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Sarkar M, Terrault N, Chan W, et al, Polycystic ovary syndrome (PCOS) is associated with NASH severity and advanced fibrosis. Liver International. October 2019 epub ahead of print.Google Scholar
  54. 54.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Jones H, Sprung VS, Pugh CJ, et al. Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2012;97(10):3709–16.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Lavery JA, Friedman AM, Keyes KM, Wright JD, Ananth CV. Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010. BJOG. 2017;124(5):804–13.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Ajmera VH, Gunderson EP, VanWagner LB, Lewis CE, Carr JJ, Terrault NA. Gestational diabetes mellitus is strongly associated with non-alcoholic fatty liver disease. Am J Gastroenterol. 2016;111(5):658–64.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Gunderson EP, Hurston SR, Ning X, et al. Lactation and progression to type 2 diabetes mellitus after gestational diabetes mellitus: a prospective cohort study. Ann Intern Med. 2015;163(12):889–98.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    • Ajmera VH, Terrault NA, VanWagner LB, et al. Longer lactation duration is associated with decreased prevalence of non-alcoholic fatty liver disease in women. J Hepatol. 2019;70(1):126–32. A longer duration of lactation, particularly greater than 6 months, is associated with lower odds of NAFLD in mid-life and may represent a modifiable risk factor for NAFLD.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Wong VW, Adams LA, de Ledinghen V, Wong GL, Sookoian S. Noninvasive biomarkers in NAFLD and NASH - current progress and future promise. Nat Rev Gastroenterol Hepatol. 2018;15(8):461–78.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Lee JH, Kim D, Kim HJ, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42(7):503–8.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol. 2005;4:10.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137(3):865–72.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Keating SE, Parker HM, Hickman IJ, et al. NAFLD in clinical practice: Can simple blood and anthropometric markers be used to detect change in liver fat measured by (1) H-MRS? Liver Int : Off J Int Assoc Stud Liver. 2017;37(12):1907–15.CrossRefGoogle Scholar
  66. 66.
    Younossi ZM, Page S, Rafiq N, et al. A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis. Obes Surg. 2011;21(4):431–9.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Sabrina N, Bai CH, Chang CC, Chien YW, Chen JR, Chang JS. Serum Iron:Ferritin Ratio Predicts Healthy Body Composition and Reduced Risk of Severe Fatty Liver in Young Adult Women. Nutrients. 2017;9(8).PubMedCentralCrossRefGoogle Scholar
  68. 68.
    Cai H, Lu S, Chen Y, et al. Serum retinol binding protein 4 and galectin-3 binding protein as novel markers for postmenopausal nonalcoholic fatty liver disease. Clin Biochem. 2018;56:95–101.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Aragones G, Auguet T, Berlanga A, et al. Increased circulating levels of alpha-ketoglutarate in morbidly obese women with non-alcoholic fatty liver disease. PLoS One. 2016;11(4):e0154601.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    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. 2006;65(1):40–4.CrossRefGoogle Scholar
  71. 71.
    Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017;13(4):220–31.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. Jama. 2002;288(3):321–33.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch Intern Med. 2006;166(3):357–65.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    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):1353–68.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Sarkar M, Yates K, Suzuki A, et al. Low testosterone is associated with nonalcoholic steatohepatitis and fibrosis severity in men with nonalcoholic fatty liver disease Digestive Diseases Week; 2019; San Diego, California.Google Scholar
  77. 77.
    Janssen I, Powell LH, Kazlauskaite R, Dugan SA. Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study. Obesity. 2010;18(3):604–10.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Lovejoy JC, Bray GA, Bourgeois MO, et al. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women--a clinical research center study. J Clin Endocrinol Metab. 1996;81(6):2198–203.PubMedGoogle Scholar
  79. 79.
    Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1–13.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Wada T, Kenmochi H, Miyashita Y, et al. Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. Endocrinology. 2010;151(5):2040–9.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Zulian E, Sartorato P, Benedini S, et al. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile. J Endocrinol Investig. 2005;28(1):49–53.CrossRefGoogle Scholar
  82. 82.
    ClinicalTrials.gov Identifier: NCT03576755.
  83. 83.
    Sharifi N, Amani R, Hajiani E, Cheraghian B. Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial. Endocrine. 2014;47(1):70–80.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Sharifi N, Amani R, Hajiani E, Cheraghian B. Women may respond different from men to vitamin D supplementation regarding cardiometabolic biomarkers. Exp Biol Med (Maywood). 2016;241(8):830–8.CrossRefGoogle Scholar
  85. 85.
    Tamargo J, Rosano G, Walther T, et al. Gender differences in the effects of cardiovascular drugs. Eur Heart J Cardiovasc Pharmacother. 2017;3(3):163–82.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Kautzky-Willer A, Harreiter J. Sex and gender differences in therapy of type 2 diabetes. Diabetes Res Clin Pract. 2017;131:230–41.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367–78 e365; quiz e314-365.CrossRefGoogle Scholar
  88. 88.
    Couchepin C, Le KA, Bortolotti M, et al. Markedly blunted metabolic effects of fructose in healthy young female subjects compared with male subjects. Diabetes Care. 2008;31(6):1254–6.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Shiferaw B, Verrill L, Booth H, et al. Sex-based differences in food consumption: Foodborne Diseases Active Surveillance Network (FoodNet) Population Survey, 2006-2007. Clin Infect Dis. 2012;54(Suppl 5):S453–7.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Vitale M, Masulli M, Cocozza S, et al. Sex differences in food choices, adherence to dietary recommendations and plasma lipid profile in type 2 diabetes - The TOSCA.IT study. Nutr Metab Cardiovasc Dis. 2016;26(10):879–85.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;47(5):711–7.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of GI/HepatologyUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Health Sciences CampusLos AngelesUSA
  3. 3.Division of Gastroenterology and HepatologyUniversity of California, San FranciscoSan FranciscoUSA

Personalised recommendations