Skip to main content

Advertisement

SpringerLink
Log in

Sexual dimorphism in hepatitis B and C and hepatocellular carcinoma

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The incidence of viral hepatitis B or C (HBV/HCV) infection and hepatocellular carcinoma is higher in male compared to female populations, showing a faster disease progression and results in a worse overall survival. Indeed, women are in general better protected from viral infections and show a lower risk of death from malignant cancer in comparison to men. Females mount stronger innate and adaptive immune responses than males, and therefore, most of the autoimmune diseases occur predominantly in females. Next to occupational and/or behavioral factors, cellular and molecular differences between the two sexes contribute to this observation. In this review, we will discuss underlying mechanisms that are important for the observed sex-related differences in liver diseases. A better appreciation of these differences between the two sexes might be of value for better and gender-specific treatment options.

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

Similar content being viewed by others

References

  1. Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L, Drake TA, Lusis AJ (2006) Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 16(8):995–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, Pawlik TM, Gores GJ (2014) Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 60(6):1268–1289

    Article  PubMed  Google Scholar 

  3. European Association for the Study of the, L (2015) EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol 63(4):971–1004

    Article  Google Scholar 

  4. Michaels RM, Rogers KD (1971) A sex difference in immunologic responsiveness. Pediatrics 47(1):120–123

    CAS  PubMed  Google Scholar 

  5. Li Z, Gadue P, Chen K, Jiao Y, Tuteja G, Schug J, Li W, Kaestner KH (2012) Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation. Cell 151(7):1608–1616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Scotland RS, Stables MJ, Madalli S, Watson P, Gilroy DW (2011) Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice. Blood 118(22):5918–5927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wikby A, Månsson IA, Johansson B, Strindhall J, Nilsson SE (2008) The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20-100 years of age. Biogerontology 9(5):299–308

    Article  PubMed  Google Scholar 

  8. Abdullah M, Chai PS, Chong MY, Tohit ERM, Ramasamy R, Pei CP, Vidyadaran S (2012) Gender effect on in vitro lymphocyte subset levels of healthy individuals. Cell Immunol 272(2):214–219

    Article  CAS  PubMed  Google Scholar 

  9. Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC (2009) Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun 10(5):509–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sankaran-Walters S, Macal M, Grishina I, Nagy L, Goulart L, Coolidge K, Li J, Fenton A, Williams T, Miller MK, Flamm J, Prindiville T, George M, Dandekar S (2013) Sex differences matter in the gut: effect on mucosal immune activation and inflammation. Biol Sex Differ 4(1):10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Furman D, Hejblum BP, Simon N, Jojic V, Dekker CL, Thiebaut R, Tibshirani RJ, Davis MM (2014) Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci U S A 111(2):869–874

    Article  CAS  PubMed  Google Scholar 

  12. Lee JH, Wang C, Kim CH (2009) FoxP3+ regulatory T cells restrain splenic extramedullary myelopoiesis via suppression of hemopoietic cytokine-producing T cells. J Immunol 183(10):6377–6386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Islami F, Goding Sauer A, Miller KD, Siegel RL, Fedewa SA, Jacobs EJ, McCullough M, Patel AV, Ma J, Soerjomataram I, Flanders WD, Brawley OW, Gapstur SM, Jemal A (2018) Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin 68(1):31–54

    Article  PubMed  Google Scholar 

  14. Xiao D, Pan H, Li F, Wu K, Zhang X, He J (2016) Analysis of ultra-deep targeted sequencing reveals mutation burden is associated with gender and clinical outcome in lung adenocarcinoma. Oncotarget 7(16):22857–22864

    Article  PubMed  PubMed Central  Google Scholar 

  15. Podolskiy DI, Lobanov AV, Kryukov GV, Gladyshev VN (2016) Analysis of cancer genomes reveals basic features of human aging and its role in cancer development. Nat Commun 7:12157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang C, Dehghani B, Li Y, Kaler LJ, Proctor T, Vandenbark AA, Offner H (2009) Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. J Immunol 182(5):3294–3303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gupta SK, Kizilbash SH, Carlson BL, Mladek AC, Boakye-Agyeman F, Bakken KK, Pokorny JL, Schroeder MA, Decker PA, Cen L, Eckel-Passow JE, Sarkar G, Ballman KV, Reid JM, Jenkins RB, Verhaak RG, Sulman EP, Kitange GJ, Sarkaria JN (2016) Delineation of MGMT hypermethylation as a biomarker for veliparib-mediated temozolomide-sensitizing therapy of glioblastoma. J Natl Cancer Inst 108(5). https://doi.org/10.1093/jnci/djv369

  18. Gupta S, Artomov M, Goggins W, Daly M, Tsao H (2015) Gender disparity and mutation burden in metastatic melanoma. J Natl Cancer Inst 107(11):djv221

    Article  PubMed  PubMed Central  Google Scholar 

  19. Huang MT, Dai YS, Chou YB, Juan YH, Wang CC, Chiang BL (2009) Regulatory T cells negatively regulate neovasculature of airway remodeling via DLL4-Notch signaling. J Immunol 183(7):4745–4754

    Article  CAS  PubMed  Google Scholar 

  20. Bianchi I, Lleo A, Gershwin ME, Invernizzi P (2012) The X chromosome and immune associated genes. J Autoimmun 38(2–3):J187–J192

    Article  CAS  PubMed  Google Scholar 

  21. Cacciari E, Masi M, Fantini MP, Licastro F, Cicognani A, Pirazzoli P, Villa MP, Specchia F, Forabosco A, Franceschi C, Martoni L (1981) Serum immunoglobulins and lymphocyte subpopulations derangement in Turner’s syndrome. J Immunogenet 8(5):337–344

    Article  CAS  PubMed  Google Scholar 

  22. Kocar IH et al (2000) The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin Exp Immunol 121(3):448–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ahn JH, Lee JT (2008) X chromosome: X inactivation. Nat Educ 1(1):24

    Google Scholar 

  24. Waxman DJ, Holloway MG (2009) Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76(2):215–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Phiel KL, Henderson RA, Adelman SJ, Elloso MM (2005) Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett 97(1):107–113

    Article  CAS  Google Scholar 

  26. Butts CL, Shukair SA, Duncan KM, Bowers E, Horn C, Belyavskaya E, Tonelli L, Sternberg EM (2007) Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int Immunol 19(3):287–296

    Article  CAS  Google Scholar 

  27. Zhao X, Liu L, Liu D, Fan H, Wang Y, Hu Y, Hou Y (2012) Progesterone enhances immunoregulatory activity of human mesenchymal stem cells via PGE2 and IL-6. Am J Reprod Immunol 68(4):290–300

    Article  CAS  PubMed  Google Scholar 

  28. Enninga EA et al (2014) Immunomodulatory effects of sex hormones: requirements for pregnancy and relevance in melanoma. Mayo Clin Proc 89(4):520–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brisken C (2013) Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer 13(6):385–396

    Article  CAS  PubMed  Google Scholar 

  30. Simon MS, Chlebowski RT, Wactawski-Wende J, Johnson KC, Muskovitz A, Kato I, Young A, Hubbell FA, Prentice RL (2012) Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol 30(32):3983–3990

    Article  PubMed  PubMed Central  Google Scholar 

  31. Skjefstad K, Richardsen E, Donnem T, Andersen S, Kiselev Y, Grindstad T, Hald SM, al-Shibli K, Bremnes RM, Busund LT, al-Saad S (2015) The prognostic role of progesterone receptor expression in non-small cell lung cancer patients: gender-related impacts and correlation with disease-specific survival. Steroids 98:29–36

    Article  CAS  PubMed  Google Scholar 

  32. Lai JJ, Lai KP, Zeng W, Chuang KH, Altuwaijri S, Chang C (2012) Androgen receptor influences on body defense system via modulation of innate and adaptive immune systems: lessons from conditional AR knockout mice. Am J Pathol 181(5):1504–1512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang SH, Chen PJ, Yeh SH (2015) Gender disparity in chronic hepatitis B: mechanisms of sex hormones. J Gastroenterol Hepatol 30(8):1237–1245

    Article  PubMed  Google Scholar 

  34. Yu MW, Chang HC, Chang SC, Liaw YF, Lin SM, Liu CJ, Lee SD, Lin CL, Chen PJ, Lin SC, Chen CJ (2003) Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B- and C-related risk. Hepatology 38(6):1393–1400

    PubMed  Google Scholar 

  35. Yasuda M, Shimizu I, Shiba M, Ito S (1999) Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. Hepatology 29(3):719–727

    Article  CAS  PubMed  Google Scholar 

  36. Sumi D, Hayashi T, Matsui-Hirai H, Jacobs AT, Ignarro LJ, Iguchi A (2003) 17beta-estradiol inhibits NADPH oxidase activity through the regulation of p47phox mRNA and protein expression in THP-1 cells. Biochim Biophys Acta 1640(2–3):113–118

    Article  CAS  PubMed  Google Scholar 

  37. Dorak MT, Karpuzoglu E (2012) Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet 3:268

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wang SH et al (2012) Estrogen receptor alpha represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4alpha. Gastroenterology 142(4):989–998 e4

    Article  CAS  PubMed  Google Scholar 

  39. Wang SH, Yeh SH, Lin WH, Wang HY, Chen DS, Chen PJ (2009) Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B. Hepatology 50(5):1392–1402

    Article  CAS  PubMed  Google Scholar 

  40. Chiu CM, Yeh SH, Chen PJ, Kuo TJ, Chang CJ, Chen PJ, Yang WJ, Chen DS (2007) Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci U S A 104(8):2571–2578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang WJ, Chang CJ, Yeh SH, Lin WH, Wang SH, Tsai TF, Chen DS, Chen PJ (2009) Hepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3beta kinase pathways. Hepatology 49(5):1515–1524

    Article  CAS  PubMed  Google Scholar 

  42. Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, Stindt J, Königer C, Nassal M, Kubitz R, Sültmann H, Urban S (2014) Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146(4):1070–1083

    Article  CAS  PubMed  Google Scholar 

  43. Cao J, Wood M, Liu Y, Hoffman T, Hyde J, Park-Sarge OK, Vore M (2004) Estradiol represses prolactin-induced expression of Na+/taurocholate cotransporting polypeptide in liver cells through estrogen receptor-alpha and signal transducers and activators of transcription 5a. Endocrinology 145(4):1739–1749

    Article  CAS  PubMed  Google Scholar 

  44. Zhao LH, Liu X, Yan HX, Li WY, Zeng X, Yang Y, Zhao J, Liu SP, Zhuang XH, Lin C, Qin CJ, Zhao Y, Pan ZY, Huang G, Liu H, Zhang J, Wang RY, Yang Y, Wen W, Lv GS, Zhang HL, Wu H, Huang S, Wang MD, Tang L, Cao HZ, Wang L, Lee TP, Jiang H, Tan YX, Yuan SX, Hou GJ, Tao QF, Xu QG, Zhang XQ, Wu MC, Xu X, Wang J, Yang HM, Zhou WP, Wang HY (2016) Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat Commun 7:12992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Klein SL, Pekosz A (2014) Sex-based biology and the rational design of influenza vaccination strategies. J Infect Dis 209(Suppl 3):S114–S119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zacharakis GH, Koskinas J, Kotsiou S, Papoutselis M, Tzara F, Vafeiadis N, Archimandritis AJ, Papoutselis K (2005) Natural history of chronic HBV infection: a cohort study with up to 12 years follow-up in North Greece (part of the Interreg I-II/EC-project). J Med Virol 77(2):173–179

    Article  CAS  PubMed  Google Scholar 

  47. Chen CJ, Yang HI, Iloeje UH, The REVEAL-HBV Study Group (2009) Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology 49(5 Suppl):S72–S84

    Article  CAS  PubMed  Google Scholar 

  48. Deng G, Zhou G, Zhai Y, Li S, Li X, Li Y, Zhang R, Yao Z, Shen Y, Qiang B, Wang Y, He F (2004) Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 40(2):318–326

    Article  CAS  PubMed  Google Scholar 

  49. Ghosh S, Klein RS (2017) Sex drives dimorphic immune responses to viral infections. J Immunol 198(5):1782–1790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16(10):626–638

    Article  CAS  Google Scholar 

  51. ECDC (2016) Hepatitis C - annual epidemiological report for 2016. [cited 2018; In 2016, 33 860 cases of hepatitis C were reported in 29 EU/EEA Member States, corresponding to a crude rate of 7.4 cases per 100 000 population. ]. Available from: https://ecdc.europa.eu/en/publications-data/hepatitis-c-annual-epidemiological-report-2016

  52. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’hUigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M (2009) Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461(7265):798–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang CC, Krantz E, Klarquist J, Krows M, McBride L, Scott EP, Shaw-Stiffel T, Weston SJ, Thiede H, Wald A, Rosen HR (2007) Acute hepatitis C in a contemporary US cohort: modes of acquisition and factors influencing viral clearance. J Infect Dis 196(10):1474–1482

    Article  PubMed  Google Scholar 

  54. Grebely J, Page K, Sacks-Davis R, van der Loeff MS, Rice TM, Bruneau J, Morris MD, Hajarizadeh B, Amin J, Cox AL, Kim AY, McGovern BH, Schinkel J, George J, Shoukry NH, Lauer GM, Maher L, Lloyd AR, Hellard M, Dore GJ, Prins M, the InC3 Study Group (2014) The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology 59(1):109–120

    Article  CAS  PubMed  Google Scholar 

  55. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ (2006) The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 144(10):705–714

    Article  PubMed  Google Scholar 

  56. Bakr I, Rekacewicz C, el Hosseiny M, Ismail S, el Daly M, el-Kafrawy S, Esmat G, Hamid MA, Mohamed MK, Fontanet A (2006) Higher clearance of hepatitis C virus infection in females compared with males. Gut 55(8):1183–1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Poynard T, Bedossa P, Opolon P (1997) Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 349(9055):825–832

    Article  CAS  PubMed  Google Scholar 

  58. Kenny-Walsh E (1999) Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 340(16):1228–1233

    Article  CAS  PubMed  Google Scholar 

  59. Wiese M, Grüngreiff K, Güthoff W, Lafrenz M, Oesen U, Porst H, East German Hepatitis C Study Group (2005) Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany--a 25-year multicenter study. J Hepatol 43(4):590–598

    Article  PubMed  Google Scholar 

  60. Wiese M, Fischer J, Löbermann M, Göbel U, Grüngreiff K, Güthoff W, Kullig U, Richter F, Schiefke I, Tenckhoff H, Zipprich A, Berg T, Müller T, for the East German HCV Study Group (2014) Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection. Hepatology 59(1):49–57

    Article  CAS  PubMed  Google Scholar 

  61. Villa E, Vukotic R, Cammà C, Petta S, di Leo A, Gitto S, Turola E, Karampatou A, Losi L, Bernabucci V, Cenci A, Tagliavini S, Baraldi E, de Maria N, Gelmini R, Bertolini E, Rendina M, Francavilla A (2012) Reproductive status is associated with the severity of fibrosis in women with hepatitis C. PLoS One 7(9):e44624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling MH, Albrecht JK (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358(9286):958–965

    Article  CAS  PubMed  Google Scholar 

  63. Wilsnack RW, Wilsnack SC, Kristjanson AF, Vogeltanz-Holm ND, Gmel G (2009) Gender and alcohol consumption: patterns from the multinational GENACIS project. Addiction 104(9):1487–1500

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hezode C et al (2003) Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study. Aliment Pharmacol Ther 17(8):1031–1037

    Article  CAS  PubMed  Google Scholar 

  65. McHutchison JG et al (2009) Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 361(6):580–593

    Article  CAS  PubMed  Google Scholar 

  66. Floreani A, Cazzagon N, Boemo DG, Baldovin T, Baldo V, Egoue J, Antoniazzi S, Minola E (2011) Female patients in fertile age with chronic hepatitis C, easy genotype, and persistently normal transaminases have a 100% chance to reach a sustained virological response. Eur J Gastroenterol Hepatol 23(11):997–1003

    PubMed  Google Scholar 

  67. Ogawa E, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Maruyama T, Tanabe Y, Satoh T, Nakamuta M, Kotoh K, Azuma K, Dohmen K, Shimoda S, Hayashi J, Kyushu University Liver Disease Study (KULDS) Group (2013) Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study. J Hepatol 58(3):495–501

    Article  CAS  PubMed  Google Scholar 

  68. Furusyo N, Ogawa E, Sudoh M, Murata M, Ihara T, Hayashi T, Ikezaki H, Hiramine S, Mukae H, Toyoda K, Taniai H, Okada K, Kainuma M, Kajiwara E, Hayashi J (2012) Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: a randomized trial. J Hepatol 57(6):1186–1192

    Article  CAS  PubMed  Google Scholar 

  69. Bioulac-Sage P et al (2013) Pathological diagnosis of hepatocellular cellular adenoma according to the clinical context. Int J Hepatol 2013:253261

    PubMed  PubMed Central  Google Scholar 

  70. Chang CY et al (2013) Changing epidemiology of hepatocellular adenoma in the United States: review of the literature. Int J Hepatol 2013:604860

    Article  PubMed  PubMed Central  Google Scholar 

  71. Bossen L, Grønbaek H, Lykke Eriksen P, Jepsen P (2017) Men with biopsy-confirmed hepatocellular adenoma have a high risk of progression to hepatocellular carcinoma: a nationwide population-based study. Liver Int 37(7):1042–1046

    Article  CAS  PubMed  Google Scholar 

  72. Farges O, Ferreira N, Dokmak S, Belghiti J, Bedossa P, Paradis V (2011) Changing trends in malignant transformation of hepatocellular adenoma. Gut 60(1):85–89

    Article  PubMed  Google Scholar 

  73. European Association for the Study of the, L. (2016) EASL clinical practice guidelines on the management of benign liver tumours. J Hepatol 65(2):386–398

    Article  Google Scholar 

  74. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317(5834):121–124

    Article  CAS  PubMed  Google Scholar 

  75. Spector LG, Johnson KJ, Soler JT, Puumala SE (2008) Perinatal risk factors for hepatoblastoma. Br J Cancer 98(9):1570–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Farinati F, Sergio A, Giacomin A, di Nolfo MA, del Poggio P, Benvegnù L, Rapaccini G, Zoli M, Borzio F, Giannini EG, Caturelli E, Trevisani F, Italian Liver Cancer group (2009) Is female sex a significant favorable prognostic factor in hepatocellular carcinoma? Eur J Gastroenterol Hepatol 21(10):1212–1218

    Article  CAS  PubMed  Google Scholar 

  77. Lee CM, Lu SN, Changchien CS, Yeh CT, Hsu TT, Tang JH, Wang JH, Lin DY, Chen CL, Chen WJ (1999) Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer 86(7):1143–1150

    Article  CAS  PubMed  Google Scholar 

  78. Xu X, Hou Y, Yin X, Bao L, Tang A, Song L, Li F, Tsang S, Wu K, Wu H, He W, Zeng L, Xing M, Wu R, Jiang H, Liu X, Cao D, Guo G, Hu X, Gui Y, Li Z, Xie W, Sun X, Shi M, Cai Z, Wang B, Zhong M, Li J, Lu Z, Gu N, Zhang X, Goodman L, Bolund L, Wang J, Yang H, Kristiansen K, Dean M, Li Y, Wang J (2012) Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 148(5):886–895

    Article  CAS  PubMed  Google Scholar 

  79. Li Z, White P, Tuteja G, Rubins N, Sackett S, Kaestner KH (2009) Foxa1 and Foxa2 regulate bile duct development in mice. J Clin Invest 119(6):1537–1545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Patrone C, Cassel TN, Pettersson K, Piao YS, Cheng G, Ciana P, Maggi A, Warner M, Gustafsson JA, Nord M (2003) Regulation of postnatal lung development and homeostasis by estrogen receptor beta. Mol Cell Biol 23(23):8542–8552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wada-Hiraike O, Hiraike H, Okinaga H, Imamov O, Barros RPA, Morani A, Omoto Y, Warner M, Gustafsson JA (2006) Role of estrogen receptor beta in uterine stroma and epithelium: insights from estrogen receptor beta-/- mice. Proc Natl Acad Sci U S A 103(48):18350–18355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wada-Hiraike O, Imamov O, Hiraike H, Hultenby K, Schwend T, Omoto Y, Warner M, Gustafsson JA (2006) Role of estrogen receptor beta in colonic epithelium. Proc Natl Acad Sci U S A 103(8):2959–2964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yu CP, Ho JY, Huang YT, Cha TL, Sun GH, Yu DS, Chang FW, Chen SP, Hsu RJ (2013) Estrogen inhibits renal cell carcinoma cell progression through estrogen receptor-beta activation. PLoS One 8(2):e56667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Passarelli MN, Phipps AI, Potter JD, Makar KW, Coghill AE, Wernli KJ, White E, Chan AT, Hutter CM, Peters U, Newcomb PA (2013) Common single-nucleotide polymorphisms in the estrogen receptor beta promoter are associated with colorectal cancer survival in postmenopausal women. Cancer Res 73(2):767–775

    Article  CAS  PubMed  Google Scholar 

  85. Press OA, Zhang W, Gordon MA, Yang D, Lurje G, Iqbal S, el-Khoueiry A, Lenz HJ (2008) Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer. Cancer Res 68(8):3037–3042

    Article  CAS  PubMed  Google Scholar 

  86. Feng H, Cheng ASL, Tsang DP, Li MS, Go MY, Cheung YS, Zhao GJ, Ng SS, Lin MC, Yu J, Lai PB, To KF, Sung JJY (2011) Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives beta-catenin/T cell factor-dependent hepatocarcinogenesis. J Clin Invest 121(8):3159–3175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ma WL, Hsu CL, Yeh CC, Wu MH, Huang CK, Jeng LB, Hung YC, Lin TY, Yeh S, Chang C (2012) Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology 56(1):176–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Han HJ, Heo JS, Lee YJ (2006) Estradiol-17beta stimulates proliferation of mouse embryonic stem cells: involvement of MAPKs and CDKs as well as protooncogenes. Am J Phys Cell Phys 290(4):C1067–C1075

    Article  CAS  Google Scholar 

  89. Nakada D, Oguro H, Levi BP, Ryan N, Kitano A, Saitoh Y, Takeichi M, Wendt GR, Morrison SJ (2014) Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 505(7484):555–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gupta PB, Proia D, Cingoz O, Weremowicz J, Naber SP, Weinberg RA, Kuperwasser C (2007) Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers. Cancer Res 67(5):2062–2071

    Article  CAS  PubMed  Google Scholar 

  91. Hartman J, Lindberg K, Morani A, Inzunza J, Strom A, Gustafsson JA (2006) Estrogen receptor beta inhibits angiogenesis and growth of T47D breast cancer xenografts. Cancer Res 66(23):11207–11213

    Article  CAS  PubMed  Google Scholar 

  92. Masuda H, Kalka C, Takahashi T, Yoshida M, Wada M, Kobori M, Itoh R, Iwaguro H, Eguchi M, Iwami Y, Tanaka R, Nakagawa Y, Sugimoto A, Ninomiya S, Hayashi S, Kato S, Asahara T (2007) Estrogen-mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis. Circ Res 101(6):598–606

    Article  CAS  PubMed  Google Scholar 

  93. Sieveking DP, Lim P, Chow RWY, Dunn LL, Bao S, McGrath KCY, Heather AK, Handelsman DJ, Celermajer DS, Ng MKC (2010) A sex-specific role for androgens in angiogenesis. J Exp Med 207(2):345–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Fish EN (2008) The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 8(9):737–744

    Article  CAS  PubMed  Google Scholar 

  95. Mode A, Gustafsson JA (2006) Sex and the liver - a journey through five decades. Drug Metab Rev 38(1–2):197–207

    Article  CAS  PubMed  Google Scholar 

  96. van Bemmel JG, Mira-Bontenbal H, Gribnau J (2016) Cis- and trans-regulation in X inactivation. Chromosoma 125(1):41–50

    Article  CAS  PubMed  Google Scholar 

  97. Northcott PA, Jones DTW, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, Pomeroy SL, Korshunov A, Lichter P, Taylor MD, Pfister SM (2012) Medulloblastomics: the end of the beginning. Nat Rev Cancer 12(12):818–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Benyoucef A, Palii CG, Wang C, Porter CJ, Chu A, Dai F, Tremblay V, Rakopoulos P, Singh K, Huang S, Pflumio F, Hébert J, Couture JF, Perkins TJ, Ge K, Dilworth FJ, Brand M (2016) UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes Dev 30(5):508–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Murakami S, Ninomiya W, Sakamoto E, Shibata T, Akiyama H, Tashiro F (2015) SRY and OCT4 are required for the acquisition of cancer stem cell-like properties and are potential differentiation therapy targets. Stem Cells 33(9):2652–2663

    Article  CAS  PubMed  Google Scholar 

  100. Murakami S, Chishima S, Uemoto H, Sakamoto E, Sato T, Kurabe N, Kawasaki Y, Shibata T, Akiyama H, Tashiro F (2014) The male-specific factor Sry harbors an oncogenic function. Oncogene 33(23):2978–2986

    Article  CAS  PubMed  Google Scholar 

  101. Kido T, Lo RCL, Li Y, Lee J, Tabatabai ZL, Ng IOL, Lau YFC (2014) The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma. Hum Pathol 45(9):1847–1858

    Article  CAS  PubMed  Google Scholar 

  102. Li S, Mo C, Huang S, Yang S, Lu Y, Peng Q, Wang J, Deng Y, Qin X, Liu Y (2014) Over-expressed testis-specific protein Y-encoded 1 as a novel biomarker for male hepatocellular carcinoma. PLoS One 9(2):e89219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lau YF, Li Y, Kido T (2009) Gonadoblastoma locus and the TSPY gene on the human Y chromosome. Birth Defects Res C Embryo Today 87(1):114–122

    Article  CAS  PubMed  Google Scholar 

  104. Kido T, Ou JH, Lau YF (2011) The X-linked tumor suppressor TSPX interacts and promotes degradation of the hepatitis B viral protein HBx via the proteasome pathway. PLoS One 6(7):e22979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tsuei DJ, Hsu HC, Lee PH, Jeng YM, Pu YS, Chen CN, Lee YC, Chou WC, Chang CJ, Ni YH, Chang MH (2004) RBMY, a male germ cell-specific RNA-binding protein, activated in human liver cancers and transforms rodent fibroblasts. Oncogene 23(34):5815–5822

    Article  CAS  PubMed  Google Scholar 

  106. Tsuei DJ, Lee PH, Peng HY, Lu SL, Su DS, Jeng YM, Hsu HC, Hsu SH, Wu JF, Ni YH, Chang MH (2011) Male germ cell-specific RNA binding protein RBMY: a new oncogene explaining male predominance in liver cancer. PLoS One 6(11):e26948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. (1998) Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet 352(9121):17–20

  108. Chou WC, Su IJ, Tien HF, Liang DC, Wang CH, Chang YC, Cheng AL (1996) Clinicopathologic, cytogenetic, and molecular studies of 13 Chinese patients with Ki-1 anaplastic large cell lymphoma. Special emphasis on the tumor response to 13-cis retinoic acid. Cancer 78(8):1805–1812

    Article  CAS  PubMed  Google Scholar 

  109. Lasset C, Bonadona V, Chauvin F, Mignotte H, Brémond A (1998) Risk of endometrial cancer in premenopausal women on tamoxifen. Lancet 352(9138):1476

    Article  CAS  PubMed  Google Scholar 

  110. Araki K, Miyazaki J, Hino O, Tomita N, Chisaka O, Matsubara K, Yamamura K (1989) Expression and replication of hepatitis B virus genome in transgenic mice. Proc Natl Acad Sci U S A 86(1):207–211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Breidbart S, Burk RD, Saenger P (1993) Hormonal regulation of hepatitis B virus gene expression: influence of androgen receptor. Pediatr Res 34(3):300–302

    Article  CAS  PubMed  Google Scholar 

  112. Chen CC, Ko TM, Ma HI, Wu HL, Xiao X, Li J, Chang CM, Wu PY, Chen CH, Han JM, Yu CP, Jeng KS, Hu CP, Tao MH (2007) Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA. Gene Ther 14(1):11–19

    Article  CAS  PubMed  Google Scholar 

  113. DeLoia JA, Burk RD, Gearhart JD (1989) Developmental regulation of hepatitis B surface antigen expression in two lines of hepatitis B virus transgenic mice. J Virol 63(9):4069–4073

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Guidotti LG, Eggers CM, Raney AK, Chi SY, Peters JM, Gonzalez FJ, McLachlan A (1999) In vivo regulation of hepatitis B virus replication by peroxisome proliferators. J Virol 73(12):10377–10386

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Julander JG, Colonno RJ, Sidwell RW, Morrey JD (2003) Characterization of antiviral activity of entecavir in transgenic mice expressing hepatitis B virus. Antivir Res 59(3):155–161

    Article  CAS  PubMed  Google Scholar 

  116. Peltekian C, Gordien E, Garreau F, Meas-Yedid V, Soussan P, Willams V, Chaix ML, Olivo-Marin JC, Bréchot C, Kremsdorf D (2005) Human MxA protein participates to the interferon-related inhibition of hepatitis B virus replication in female transgenic mice. J Hepatol 43(6):965–972

    Article  CAS  PubMed  Google Scholar 

  117. Buzzetti E, Parikh PM, Gerussi A, Tsochatzis E (2017) Gender differences in liver disease and the drug-dose gender gap. Pharmacol Res 120:97–108

    Article  CAS  PubMed  Google Scholar 

  118. Carbone M, Mells GF, Pells G, Dawwas MF, Newton JL, Heneghan MA, Neuberger JM, Day DB, Ducker SJ, UK PBC Consortium, Sandford RN, Alexander GJ, Jones DE (2013) Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 144(3):560–569 e7 quiz e13–4

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany

    Nico Buettner & Robert Thimme

Authors
  1. Nico Buettner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Thimme
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Thimme.

Additional information

This article is a contribution to the special issue on Sexual Dimorphism in Immunity - Guest Editors: Hanna Lotter and Marcus Altfed

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Buettner, N., Thimme, R. Sexual dimorphism in hepatitis B and C and hepatocellular carcinoma. Semin Immunopathol 41, 203–211 (2019). https://doi.org/10.1007/s00281-018-0727-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-018-0727-4

Keywords

Search

Navigation