Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database

1. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841–55. doi: 10.1093/humrep/dew218 27664216.

2. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004 Jan; 81(1): 19–25 14711538

3. Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab. 2010;95(5):2038–49. doi: 10.1210/jc.2009-2724 20375205.

4. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28–38 e25. doi: 10.1016/j.fertnstert.2011.09.024 22153789.

5. O'Reilly MW, Taylor AE, Crabtree NJ, Hughes BA, Capper F, Crowley RK, et al. Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. J Clin Endocrinol Metab. 2014;99(3):1027–36. doi: 10.1210/jc.2013-3399 24423344; PubMed Central PMCID: PMC3955250.

6. Dewailly D, Catteau-Jonard S, Reyss AC, Leroy M, Pigny P. Oligoanovulation with polycystic ovaries but not overt hyperandrogenism. J Clin Endocrinol Metab. 2006;91(10):3922–7. doi: 10.1210/jc.2006-1054 16849400.

7. O'Reilly MW, Kempegowda P, Jenkinson C, Taylor AE, Quanson JL, Storbeck KH, et al. 11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017;102(3):840–8. doi: 10.1210/jc.2016-3285 27901631.

8. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi: 10.1002/hep.28431 26707365.

9. Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM. 2010;103(2):71–83. doi: 10.1093/qjmed/hcp158 19914930; PubMed Central PMCID: PMC2810391.

10. Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014;59(3):1174–97. doi: 10.1002/hep.26717 24002776.

11. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–55. doi: 10.1053/j.gastro.2014.11.039 25461851.

12. Jelenik T, Kaul K, Sequaris G, Flogel U, Phielix E, Kotzka J, et al. Mechanisms of Insulin Resistance in Primary and Secondary Non-Alcoholic Fatty Liver. Diabetes. 2017. doi: 10.2337/db16-1147 28490610.

13. Ramezani-Binabaj M, Motalebi M, Karimi-Sari H, Rezaee-Zavareh MS, Alavian SM. Are women with polycystic ovarian syndrome at a high risk of non-alcoholic Fatty liver disease; a meta-analysis. Hepat Mon. 2014;14(11):e23235. doi: 10.5812/hepatmon.23235 25598791; PubMed Central PMCID: PMC4286712.

14. Vassilatou E, Vassiliadi DA, Salambasis K, Lazaridou H, Koutsomitopoulos N, Kelekis N, et al. Increased prevalence of polycystic ovary syndrome in premenopausal women with nonalcoholic fatty liver disease. Eur J Endocrinol. 2015;173(6):739–47. doi: 10.1530/EJE-15-0567 26340970.

15. Romanowski MD, Parolin MB, Freitas AC, Piazza MJ, Basso J, Urbanetz AA. Prevalence of non-alcoholic fatty liver disease in women with polycystic ovary syndrome and its correlation with metabolic syndrome. Arq Gastroenterol. 2015;52(2):117–23. doi: 10.1590/S0004-28032015000200008 26039829.

16. Vassilatou E, Lafoyianni S, Vryonidou A, Ioannidis D, Kosma L, Katsoulis K, et al. Increased androgen bioavailability is associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome. Hum Reprod. 2010;25(1):212–20. doi: 10.1093/humrep/dep380 19887498.

17. Cai J, Wu CH, Zhang Y, Wang YY, Xu WD, Lin TC, et al. High-free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independent of obesity and insulin resistance. Int J Obes (Lond). 2017. doi: 10.1038/ijo.2017.116 28487551.

18. Kim JJ, Kim D, Yim JY, Kang JH, Han KH, Kim SM, et al. Polycystic ovary syndrome with hyperandrogenism as a risk factor for non-obese non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2017;45(11):1403–12. doi: 10.1111/apt.14058 28370150.

19. Rocha ALL, Faria LC, Guimaraes TCM, Moreira GV, Candido AL, Couto CA, et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta-analysis. J Endocrinol Invest. 2017; 40(12): 1279–1288 doi: 10.1007/s40618-017-0708-9 28612285.

20. Booth N. What are the Read Codes? Health Libr Rev. 1994;11(3):177–82. 10139676.

21. Sammon CJ, Petersen I. Backdating of events in electronic primary health care data: should one censor at the date of last data collection. Pharmacoepidemiol Drug Saf. 2016;25(4):378–84. doi: 10.1002/pds.3981 26887352.

22. Blak BT, Thompson M, Dattani H, Bourke A. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Inform Prim Care. 2011;19(4):251–5. 22828580.

23. Ding T, Baio G, Hardiman PJ, Petersen I, Sammon C. Diagnosis and management of polycystic ovary syndrome in the UK (2004–2014): a retrospective cohort study. BMJ Open. 2016;6(7):e012461. doi: 10.1136/bmjopen-2016-012461 27401369; PubMed Central PMCID: PMC4947736.

24. Loomis AK, Kabadi S, Preiss D, Hyde C, Bonato V, St Louis M, et al. Body Mass Index and Risk of Nonalcoholic Fatty Liver Disease: Two Electronic Health Record Prospective Studies. J Clin Endocrinol Metab. 2016;101(3):945–52. doi: 10.1210/jc.2015-3444 26672639; PubMed Central PMCID: PMC4803162.

25. Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Rev. 2013;14(2):95–109. doi: 10.1111/j.1467-789X.2012.01053.x 23114091.

26. Li L, Liu DW, Yan HY, Wang ZY, Zhao SH, Wang B. Obesity is an independent risk factor for non-alcoholic fatty liver disease: evidence from a meta-analysis of 21 cohort studies. Obes Rev. 2016;17(6):510–9. doi: 10.1111/obr.12407 27020692.

27. Karim ME, Gustafson P, Petkau J, Tremlett H, Long-Term Benefits Adverse Effects of Beta-Interferon for Multiple Sclerosis Study Group, Karim ME, et al. Comparison of Statistical Approaches for Dealing With Immortal Time Bias in Drug Effectiveness Studies. Am J Epidemiol. 2016;184(4):325–35. doi: 10.1093/aje/kwv445 27455963; PubMed Central PMCID: PMC4983651.

28. Dave S, Petersen I. Creating medical and drug code lists to identify cases in primary care databases. Pharmacoepidemiol Drug Saf. 2009;18(8):704–7. doi: 10.1002/pds.1770 19455565.

29. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2015;350:h2135. doi: 10.1136/bmj.h2135 26013557; PubMed Central PMCID: PMC4444976.

30. Townsend P. Deprivation. Journal of Social Policy. 1987;16(2):125–46.

31. Keane MG, Horsfall LJ, Rait G, Pereira SP. Sociodemographic trends in the incidence of pancreatic and biliary tract cancer in UK primary care. PLoS ONE. 2014;9(9):e108498. doi: 10.1371/journal.pone.0108498 25268478; PubMed Central PMCID: PMC4182488.

32. Glintborg D, Hass Rubin K, Nybo M, Abrahamsen B, Andersen M. Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome. Eur J Endocrinol. 2015;172(5):627–38. doi: 10.1530/EJE-14-1108 25656495.

33. Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ. 1995;310(6973):170. 7833759; PubMed Central PMCID: PMC2548561.

34. Benchimol EI, Smeeth L, Guttmann A, Harron K, Moher D, Petersen I, et al. The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. PLoS Med. 2015;12(10):e1001885. doi: 10.1371/journal.pmed.1001885 26440803; PubMed Central PMCID: PMC4595218.

35. Delgado-Rodriguez M, Llorca J. Bias. J Epidemiol Community Health. 2004;58(8):635–41. doi: 10.1136/jech.2003.008466 15252064; PubMed Central PMCID: PMC1732856.

36. Petersen I, Collings SL, McCrea RL, Nazareth I, Osborn DP, Cowen PJ, et al. Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies. Clin Epidemiol. 2017;9:95–103. doi: 10.2147/CLEP.S118336 28243149; PubMed Central PMCID: PMC5317245.

37. Hazlehurst JM, Tomlinson JW. Non-alcoholic fatty liver disease in common endocrine disorders. Eur J Endocrinol. 2013;169(2):R27–37. doi: 10.1530/EJE-13-0296 23653455.

38. Chen MJ, Chiu HM, Chen CL, Yang WS, Yang YS, Ho HN. Hyperandrogenemia is independently associated with elevated alanine aminotransferase activity in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95(7):3332–41. doi: 10.1210/jc.2009-2698 20427499.

39. Jones H, Sprung VS, Pugh CJ, Daousi C, Irwin A, Aziz N, 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. doi: 10.1210/jc.2012-1382 22837189.

40. Sarkar M, Wellons M, Cedars MI, VanWagner L, Gunderson EP, Ajmera V, 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. doi: 10.1038/ajg.2017.44 28291240.

41. O'Reilly MW, Kempegowda P, Walsh M, Taylor AE, Manolopoulos KN, Allwood JW, et al. AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2017. doi: 10.1210/jc.2017-00947 28645211.

42. Anjani K, Lhomme M, Sokolovska N, Poitou C, Aron-Wisnewsky J, Bouillot JL, et al. Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity. J Hepatol. 2015;62(4):905–12. doi: 10.1016/j.jhep.2014.11.002 25450212.

43. Nasiri M, Nikolaou N, Parajes S, Krone NP, Valsamakis G, Mastorakos G, et al. 5alpha-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes. Endocrinology. 2015;156(8):2863–71. doi: 10.1210/en.2015-1149 25974403; PubMed Central PMCID: PMC4511138.

44. Schiffer L, Kempegowda P, Arlt W, O'Reilly MW. MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease. Eur J Endocrinol. 2017. doi: 10.1530/EJE-17-0124 28566439.

45. 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. doi: 10.5604/16652681.1235481 28425408.

46. Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA. Interactions of sex hormone-binding globulin with target cells. Molecular and cellular endocrinology. 2010;316(1):79–85. doi: 10.1016/j.mce.2009.08.009 19698759.

47. Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S. Genetic syndromes of severe insulin resistance. Endocr Rev. 2011;32(4):498–514. doi: 10.1210/er.2010-0020 21536711.

48. Franks S. Polycystic ovary syndrome. N Engl J Med. 1995;333(13):853–61. doi: 10.1056/NEJM199509283331307 7651477.

49. Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, et al. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev. 2012;33(5):812–41. doi: 10.1210/er.2012-1003 22829562; PubMed Central PMCID: PMC3461136.

50. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6):774–800. doi: 10.1210/edrv.18.6.0318 9408743.

51. Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017;14(1):32–42. doi: 10.1038/nrgastro.2016.147 27729660.

52. Li S, Chu Q, Ma J, Sun Y, Tao T, Huang R, et al. Discovery of Novel Lipid Profiles in PCOS: Do Insulin and Androgen Oppositely Regulate Bioactive Lipid Production? J Clin Endocrinol Metab. 2017;102(3):810–21. doi: 10.1210/jc.2016-2692 27886515.

53. Cassar S, Teede HJ, Harrison CL, Joham AE, Moran LJ, Stepto NK. Biomarkers and insulin sensitivity in women with Polycystic Ovary Syndrome: Characteristics and predictive capacity. Clin Endocrinol (Oxf). 2015;83(1):50–8. doi: 10.1111/cen.12619 25262763.

54. Byrne CD, Targher G. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease: is universal screening appropriate? Diabetologia. 2016;59(6):1141–4. doi: 10.1007/s00125-016-3910-y 27053232.