Hemostatic and Fibrinolytic Abnormalities in Polycystic Ovary Syndrome^[*]

 

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Abstract

Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility, affecting up to 10% of women of reproductive age. This syndrome was first described in 1935 when American gynecologists Stein and Leventhal associated the presence of ovarian cysts with anovulation, obesity, and hirsutism. For many years, the effects of PCOS on coagulation and fibrinolysis have remained largely unexplored. This review summarizes current knowledge of the effects of PCOS on coagulation and fibrinolysis, and the putative mechanisms by which PCOS may contribute to the development of coagulation and fibrinolytic disorders. To date, there is relatively strong evidence suggesting that PCOS is associated with increased platelet aggregation and decreased plasma fibrinolytic activity. However, whether these hemostatic disorders are linked to the abnormal hormonal system in PCOS remains to be elucidated. Moreover, it should be emphasized that PCOS is a heterogeneous endocrine condition, and that the number of published studies is limited, the sample size of most of these studies is relatively small, and the selection of control subjects has not been always appropriate. Furthermore, well-designed studies on larger cohorts of carefully characterized PCOS patients are needed to provide more comprehensive information on this issue.

^* This article is dedicated to my father, Gianfranco Targher (1940–1996), my first and most important mentor.

• References

• 1 Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol 2013; 6: 1-13
  PubMedGoogle Scholar
• 2 Mak W, Dokras A. Polycystic ovarian syndrome and the risk of cardiovascular disease and thrombosis. Semin Thromb Hemost 2009; 35 (7) 613-620
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Targher G, Pichiri I, Zoppini G, Bonora E, Chonchol M. Hemostatic and fibrinolytic abnormalities in endocrine diseases: a narrative review. Semin Thromb Hemost 2009; 35 (7) 605-612
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29: 181-191
  PubMedGoogle Scholar
• 5 Hanson AE. Hippocrates: Diseases of Women 1. Signs (Chic) 1975; 1: 567-584
  CrossrefPubMedGoogle Scholar
• 6 Temkin O. Soranus' Gynecology. Book I. Baltimore, MA: The Johns Hopkins University Press; 1991
  Google Scholar
• 7 Vallisneri A. Istoria della generazione dell'uomo, e degli animali, se sia da' vermicelli spermatici, o dalle uova: con un trattato nel fine della sterilità, e de' suoi rimedj; con la critica de' superflui, e de' nocivi; con un discorso accademico intorno la connessione di tutte le cose create; e con alcune lettere, istorie rare, osservazioni d'uomini illustri. Gio. Gabbriel Hertz ed., Venice 1721: 146
  Google Scholar
• 8 Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19 (1) 41-47
  CrossrefPubMedGoogle Scholar
• 9 Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, , eds. Polycystic Ovary Syndrome. Boston, MA: Blackwell Scientific Publications; 1992: 377-384
  Google Scholar
• 10 March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010; 25 (2) 544-551
  Google Scholar
• 11 Yildiz BO, Bozdag G, Yapici Z, Esinler I, Yarali H. Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum Reprod 2012; 27 (10) 3067-3073
  CrossrefPubMedGoogle Scholar
• 12 Azziz R, Carmina E, Dewailly D , et al; Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91 (11) 4237-4245
  Google Scholar
• 13 Moghetti P, Tosi F, Bonin C , et al. Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. J Clin Endocrinol Metab 2013; 98 (4) E628-E637
  CrossrefPubMedGoogle Scholar
• 14 Legro RS, Arslanian SA, Ehrmann DA , et al; Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013; 98 (12) 4565-4592
  CrossrefPubMedGoogle Scholar
• 15 Kelly CJG, Lyall H, Petrie JR , et al. A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2002; 87 (7) 3287-3290
  CrossrefPubMedGoogle Scholar
• 16 Dereli D, Ozgen G, Buyukkececi F, Guney E, Yilmaz C. Platelet dysfunction in lean women with polycystic ovary syndrome and association with insulin sensitivity. J Clin Endocrinol Metab 2003; 88 (5) 2263-2268
  CrossrefPubMedGoogle Scholar
• 17 Gursoy A, Ertugrul DT, Pamuk B , et al. Mean platelet volume in patients with polycystic ovary disease. Platelets 2006; 17 (7) 505-506
  CrossrefPubMedGoogle Scholar
• 18 Oktem M, Ozcimen EE, Uckuyu A , et al. Polycystic ovary syndrome is associated with elevated plasma soluble CD40 ligand, a marker of coronary artery disease. Fertil Steril 2009; 91 (6) 2545-2550
  CrossrefPubMedGoogle Scholar
• 19 Rajendran S, Willoughby SR, Chan WPA , et al. Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects. Atherosclerosis 2009; 204 (2) 509-514
  CrossrefPubMedGoogle Scholar
• 20 Moran LJ, Hutchison SK, Meyer C, Zoungas S, Teede HJ. A comprehensive assessment of endothelial function in overweight women with and without polycystic ovary syndrome. Clin Sci (Lond) 2009; 116 (10) 761-770
  CrossrefPubMedGoogle Scholar
• 21 Kebapcilar L, Taner CE, Kebapcilar AG, Sari I. High mean platelet volume, low-grade systemic coagulation and fibrinolytic activation are associated with androgen and insulin levels in polycystic ovary syndrome. Arch Gynecol Obstet 2009; 280 (2) 187-193
  CrossrefPubMedGoogle Scholar
• 22 Luque-Ramírez M, Mendieta-Azcona C, del Rey Sánchez JM, Matíes M, Escobar-Morreale HF. Effects of an antiandrogenic oral contraceptive pill compared with metformin on blood coagulation tests and endothelial function in women with the polycystic ovary syndrome: influence of obesity and smoking. Eur J Endocrinol 2009; 160 (3) 469-480
  CrossrefPubMedGoogle Scholar
• 23 Yildiz BO, Bozdag G, Harmanci A , et al. Increased circulating soluble P-selectin in polycystic ovary syndrome. Fertil Steril 2010; 93 (7) 2311-2315
  CrossrefPubMedGoogle Scholar
• 24 Mannerås-Holm L, Baghaei F, Holm G , et al. Coagulation and fibrinolytic disturbances in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2011; 96 (4) 1068-1076
  CrossrefPubMedGoogle Scholar
• 25 Koiou E, Tziomalos K, Katsikis I , et al. Plasma von Willebrand factor antigen levels are elevated in the classic phenotypes of polycystic ovary syndrome. Hormones (Athens) 2012; 11 (1) 77-85
  PubMedGoogle Scholar
• 26 Koiou E, Tziomalos K, Katsikis I, Papadakis E, Kandaraki EA, Panidis D. Platelet-derived microparticles in overweight/obese women with the polycystic ovary syndrome. Gynecol Endocrinol 2013; 29 (3) 250-253
  CrossrefPubMedGoogle Scholar
• 27 Kahal H, Aburima A, Ungvari T , et al. Polycystic ovary syndrome has no independent effect on vascular, inflammatory or thrombotic markers when matched for obesity. Clin Endocrinol (Oxf) 2013; 79 (2) 252-258
  CrossrefPubMedGoogle Scholar
• 28 Atiomo WU, Bates SA, Condon JE, Shaw S, West JH, Prentice AG. The plasminogen activator system in women with polycystic ovary syndrome. Fertil Steril 1998; 69 (2) 236-241
  CrossrefPubMedGoogle Scholar
• 29 Yildiz BO, Haznedaroğlu IC, Kirazli S, Bayraktar M. Global fibrinolytic capacity is decreased in polycystic ovary syndrome, suggesting a prothrombotic state. J Clin Endocrinol Metab 2002; 87 (8) 3871-3875
  CrossrefPubMedGoogle Scholar
• 30 Słopień R, Lewandowski K, Kolacz E, Zawilska K, Warenik-Szymankiewicz A. Comparison of fibrinolytic and metabolic system parameters in obese patients with polycystic ovary syndrome and women with simple obesity. Gynecol Endocrinol 2006; 22 (11) 651-654
  CrossrefPubMedGoogle Scholar
• 31 Erdoğan M, Karadeniz M, Alper GE , et al. Thrombin-activatable fibrinolysis inhibitor and cardiovascular risk factors in polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2008; 116 (3) 143-147
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Karakurt F, Gumus II, Bavbek N , et al. Increased thrombin-activatable fibrinolysis inhibitor antigen levels as a clue for prothrombotic state in polycystic ovary syndrome. Gynecol Endocrinol 2008; 24 (9) 491-497
  CrossrefPubMedGoogle Scholar
• 33 Oral B, Mermi B, Dilek M, Alanoğlu G, Sütçü R. Thrombin activatable fibrinolysis inhibitor and other hemostatic parameters in patients with polycystic ovary syndrome. Gynecol Endocrinol 2009; 25 (2) 110-116
  CrossrefPubMedGoogle Scholar
• 34 González F, Kirwan JP, Rote NS, Minium J. Elevated circulating levels of tissue factor in polycystic ovary syndrome. Clin Appl Thromb Hemost 2013; 19 (1) 66-72
  CrossrefPubMedGoogle Scholar
• 35 de Mendonça-Louzeiro MRMF, Annichino-Bizzacchi JM, Magna LA, Quaino SK, Benetti-Pinto CL. Faster thrombin generation in women with polycystic ovary syndrome compared with healthy controls matched for age and body mass index. Fertil Steril 2013; 99 (6) 1786-1790
  CrossrefPubMedGoogle Scholar
• 36 Sampson M, Kong C, Patel A, Unwin R, Jacobs HS. Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol (Oxf) 1996; 45 (5) 623-629
  CrossrefPubMedGoogle Scholar
• 37 Atiomo WU, Fox R, Condon JE , et al. Raised plasminogen activator inhibitor-1 (PAI-1) is not an independent risk factor in the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2000; 52 (4) 487-492
  CrossrefPubMedGoogle Scholar
• 38 Tarkun I, Cantürk Z, Arslan BC, Türemen E, Tarkun P. The plasminogen activator system in young and lean women with polycystic ovary syndrome. Endocr J 2004; 51 (5) 467-472
  CrossrefPubMedGoogle Scholar
• 39 Diamanti-Kandarakis E, Palioniko G, Alexandraki K, Bergiele A, Koutsouba T, Bartzis M. The prevalence of 4G5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene in polycystic ovarian syndrome and its association with plasma PAI-1 levels. Eur J Endocrinol 2004; 150 (6) 793-798
  CrossrefPubMedGoogle Scholar
• 40 Orio Jr F, Palomba S, Cascella T , et al. Is plasminogen activator inhibitor-1 a cardiovascular risk factor in young women with polycystic ovary syndrome?. Reprod Biomed Online 2004; 9 (5) 505-510
  CrossrefPubMedGoogle Scholar
• 41 Carmassi F, De Negri F, Fioriti R , et al. Insulin resistance causes impaired vasodilation and hypofibrinolysis in young women with polycystic ovary syndrome. Thromb Res 2005; 116 (3) 207-214
  CrossrefPubMedGoogle Scholar
• 42 Lin S, Yongmei G. Plasminogen activator and plasma activator inhibitor-1 in young women with polycystic ovary syndrome. Int J Gynaecol Obstet 2008; 100 (3) 285-286
  CrossrefPubMedGoogle Scholar
• 43 Lin S, Huiya Z, Bo L, Wei W, Yongmei G. The plasminogen activator inhibitor-1 (PAI-1) gene -844 A/G and -675 4G/5G promoter polymorphism significantly influences plasma PAI-1 levels in women with polycystic ovary syndrome. Endocrine 2009; 36 (3) 503-509
  CrossrefPubMedGoogle Scholar
• 44 González F, Rote NS, Minium J, Kirwan JP. Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism 2009; 58 (7) 954-962
  CrossrefPubMedGoogle Scholar
• 45 Lindholm A, Bixo M, Eliasson M , et al. Tissue plasminogen activator and plasminogen activator inhibitor 1 in obese and lean patients with polycystic ovary syndrome. Gynecol Endocrinol 2010; 26 (10) 743-748
  CrossrefPubMedGoogle Scholar
• 46 Koiou E, Tziomalos K, Dinas K , et al. Plasma plasminogen activator inhibitor-1 levels in the different phenotypes of the polycystic ovary syndrome. Endocr J 2012; 59 (1) 21-29
  CrossrefPubMedGoogle Scholar
• 47 Atiomo WU, Condon J, Adekanmi O, Friend J, Wilkin TJ, Prentice AG. Are women with polycystic ovary syndrome resistant to activated protein C?. Fertil Steril 2000; 74 (6) 1229-1232
  CrossrefPubMedGoogle Scholar
• 48 Tsanadis G, Vartholomatos G, Korkontzelos I , et al. Polycystic ovarian syndrome and thrombophilia. Hum Reprod 2002; 17 (2) 314-319
  CrossrefPubMedGoogle Scholar
• 49 Adali E, Yildizhan R, Kurdoglu M, Bugdayci G, Kolusari A, Sahin HG. Increased plasma thrombin-activatable fibrinolysis inhibitor levels in young obese women with polycystic ovary syndrome. Fertil Steril 2010; 94 (2) 666-672
  CrossrefPubMedGoogle Scholar
• 50 Moini A, Tadayon S, Tehranian A, Yeganeh LM, Akhoond MR, Yazdi RS. Association of thrombophilia and polycystic ovarian syndrome in women with history of recurrent pregnancy loss. Gynecol Endocrinol 2012; 28 (8) 590-593
  CrossrefPubMedGoogle Scholar
• 51 Heutling D, Schulz H, Nickel I , et al. Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment. J Clin Endocrinol Metab 2008; 93 (1) 82-90
  CrossrefPubMedGoogle Scholar
• 52 Charitidou C, Farmakiotis D, Zournatzi V , et al. The administration of estrogens, combined with anti-androgens, has beneficial effects on the hormonal features and asymmetric dimethyl-arginine levels, in women with the polycystic ovary syndrome. Atherosclerosis 2008; 196 (2) 958-965
  CrossrefPubMedGoogle Scholar
• 53 Pamuk BO, Torun AN, Kulaksizoglu M , et al. Asymmetric dimethylarginine levels and carotid intima-media thickness in obese patients with polycystic ovary syndrome and their relationship to metabolic parameters. Fertil Steril 2010; 93 (4) 1227-1233
  CrossrefPubMedGoogle Scholar
• 54 Burchall G, Linden MD, Teede H, Piva TJ. Hemostatic abnormalities and relationships to metabolic and hormonal status in polycystic ovarian syndrome. Trends Cardiovasc Med 2011; 21 (1) 6-14
  CrossrefPubMedGoogle Scholar
• 55 Diamanti-Kandarakis E, Paterakis T, Kandarakis HA. Indices of low-grade inflammation in polycystic ovary syndrome. Ann N Y Acad Sci 2006; 1092: 175-186
  CrossrefPubMedGoogle Scholar
• 56 Pai JK, Pischon T, Ma J , et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004; 351 (25) 2599-2610
  CrossrefPubMedGoogle Scholar
• 57 Haverkate F. Levels of haemostatic factors, arteriosclerosis and cardiovascular disease. Vascul Pharmacol 2002; 39 (3) 109-112
  CrossrefPubMedGoogle Scholar
• 58 Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertil Steril 2011; 95 (3) 1048-1058 , e1–e2
  Google Scholar
• 59 Ciaraldi TP, Aroda V, Mudaliar SR, Henry RR. Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment. Metabolism 2013; 62 (11) 1587-1596
  CrossrefPubMedGoogle Scholar
• 60 Olufadi R, Byrne CD. Effects of VLDL and remnant particles on platelets. Pathophysiol Haemost Thromb 2006; 35 (3-4) 281-291
  CrossrefPubMedGoogle Scholar
• 61 Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res 2006; 98 (11) 1352-1364
  CrossrefPubMedGoogle Scholar
• 62 Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP. Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol Metab 2007; 18 (7) 280-285
  CrossrefPubMedGoogle Scholar
• 63 Roe A, Hillman J, Butts S , et al. Decreased cholesterol efflux capacity and atherogenic lipid profile in young women with PCOS. J Clin Endocrinol Metab 2014; 99 (5) E841-E847
  CrossrefPubMedGoogle Scholar
• 64 Kim JJ, Choi YM. Dyslipidemia in women with polycystic ovary syndrome. Obstet Gynecol Sci 2013; 56 (3) 137-142
  CrossrefPubMedGoogle Scholar
• 65 Chen Y, Billadello JJ, Schneider DJ. Identification and localization of a fatty acid response region in the human plasminogen activator inhibitor-1 gene. Arterioscler Thromb Vasc Biol 2000; 20 (12) 2696-2701
  CrossrefPubMedGoogle Scholar
• 66 Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10 (6) 330-344
  CrossrefPubMedGoogle Scholar
• 67 Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363 (14) 1341-1350
  CrossrefPubMedGoogle Scholar
• 68 Targher G, Byrne CD. Diagnosis and management of nonalcoholic fatty liver disease and its hemostatic/thrombotic and vascular complications. Semin Thromb Hemost 2013; 39 (2) 214-228
  Article in Thieme ConnectPubMedGoogle Scholar
• 69 Targher G, Zoppini G, Moghetti P, Day CP. Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Semin Thromb Hemost 2010; 36 (1) 41-48
  Article in Thieme ConnectPubMedGoogle Scholar
• 70 Karoli R, Fatima J, Chandra A, Gupta U, Islam FU, Singh G. Prevalence of hepatic steatosis in women with polycystic ovary syndrome. J Hum Reprod Sci 2013; 6 (1) 9-14
  CrossrefPubMedGoogle Scholar
• 71 Baranova A, Tran TP, Birerdinc A, Younossi ZM. Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2011; 33 (7) 801-814
  CrossrefPubMedGoogle Scholar
• 72 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) 3709-3716
  CrossrefPubMedGoogle Scholar
• 73 Carmina E. Obesity, adipokines and metabolic syndrome in polycystic ovary syndrome. Front Horm Res 2013; 40: 40-50
  PubMedGoogle Scholar
• 74 Gupta V, Bhasin S, Guo W , et al. Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes. Mol Cell Endocrinol 2008; 296 (1-2) 32-40
  CrossrefPubMedGoogle Scholar
• 75 Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132 (6) 2169-2180
  CrossrefPubMedGoogle Scholar
• 76 Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: mechanisms and epidemiology. Thromb Haemost 2013; 110 (4) 669-680
  Article in Thieme ConnectPubMedGoogle Scholar
• 77 Stegenga ME, van der Crabben SN, Levi M , et al. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes 2006; 55 (6) 1807-1812
  CrossrefPubMedGoogle Scholar
• 78 Allan CA. Sex steroids and glucose metabolism. Asian J Androl 2014; 16 (2) 232-238
  CrossrefPubMedGoogle Scholar
• 79 Setji TL, Brown AJ. Polycystic ovary syndrome: update on diagnosis and treatment. Am J Med 2014; (e-pub ahead of print) doi: 0.1016/j.amjmed.2014.04.017
  PubMedGoogle Scholar
• 80 Devin JK, Johnson JE, Eren M , et al. Transgenic overexpression of plasminogen activator inhibitor-1 promotes the development of polycystic ovarian changes in female mice. J Mol Endocrinol 2007; 39 (1) 9-16
  CrossrefPubMedGoogle Scholar
• 81 Kyei-Mensah AA, LinTan S, Zaidi J, Jacobs HS. Relationship of ovarian stromal volume to serum androgen concentrations in patients with polycystic ovary syndrome. Hum Reprod 1998; 13 (6) 1437-1441
  CrossrefPubMedGoogle Scholar
• 82 Kebapcilar L, Taner CE, Kebapcilar AG, Alacacioglu A, Sari I. Comparison of four different treatment regimens on coagulation parameters, hormonal and metabolic changes in women with polycystic ovary syndrome. Arch Gynecol Obstet 2010; 281 (1) 35-42
  CrossrefPubMedGoogle Scholar
• 83 Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 2003; 24 (2) 183-217
  CrossrefPubMedGoogle Scholar
• 84 Escobar-Morreale HF, Carmina E, Dewailly D , et al. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2012; 18 (2) 146-170
  CrossrefPubMedGoogle Scholar
• 85 Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008; 23 (3) 462-477
  CrossrefPubMedGoogle Scholar
• 86 Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev 2012; 5: CD003053
  Google Scholar
• 87 Legro RS, Barnhart HX, Schlaff WD , et al; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356 (6) 551-566
  CrossrefPubMedGoogle Scholar
• 88 Moghetti P. For what reasons should metformin be used in the management of polycystic ovary syndrome?. J Endocrinol Invest 2012; 35 (1) 87-89
  PubMedGoogle Scholar
• 89 Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014; 10 (3) 143-156
  CrossrefPubMedGoogle Scholar
• 90 Wild RA, Carmina E, Diamanti-Kandarakis E , 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) 2038-2049
  CrossrefPubMedGoogle Scholar
• 91 Tanis BC, van den Bosch MA, Kemmeren JM , et al. Oral contraceptives and the risk of myocardial infarction. N Engl J Med 2001; 345 (25) 1787-1793
  CrossrefPubMedGoogle Scholar
• 92 Kaunitz AM. Clinical practice. Hormonal contraception in women of older reproductive age. N Engl J Med 2008; 358 (12) 1262-1270
  CrossrefPubMedGoogle Scholar
• 93 Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol 2009; 8 (11) 998-1005
  CrossrefPubMedGoogle Scholar
• 94 Petitti DB. Hormonal contraceptives and arterial thrombosis—not risk-free but safe enough. N Engl J Med 2012; 366 (24) 2316-2318
  CrossrefPubMedGoogle Scholar
• 95 Petitti DB. Clinical practice. Combination estrogen-progestin oral contraceptives. N Engl J Med 2003; 349 (15) 1443-1450
  CrossrefPubMedGoogle Scholar
• 96 van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009; 339: b2921
  CrossrefPubMedGoogle Scholar
• 97 Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011; 343: d6423
  CrossrefPubMedGoogle Scholar
• 98 Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 2011; 342: d2151
  CrossrefPubMedGoogle Scholar
• 99 Parkin L, Sharples K, Hernandez RK, Jick SS. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 2011; 342: d2139
  CrossrefPubMedGoogle Scholar
• 100 Seaman HE, de Vries CS, Farmer RD. The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case-control study. Hum Reprod 2003; 18 (3) 522-526
  CrossrefPubMedGoogle Scholar
• 101 Okoroh EM, Hooper WC, Atrash HK, Yusuf HR, Boulet SL. Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003–2008. Am J Obstet Gynecol 2012; 207: 377.e1-8
  CrossrefPubMedGoogle Scholar
• 102 Andersen P, Seljeflot I, Abdelnoor M , et al. Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism 1995; 44 (5) 611-616
  CrossrefPubMedGoogle Scholar
• 103 Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997; 46 (4) 454-457
  CrossrefPubMedGoogle Scholar
• 104 Serdyńska-Szuster M, Banaszewska B, Spaczyński R, Pawelczyk L. Effects of metformin therapy on markers of coagulation disorders in hyperinsulinemic women with polycystic ovary syndrome [in Polish]. Ginekol Pol 2011; 82 (4) 259-264
  PubMedGoogle Scholar
• 105 de Jager J, Kooy A, Schalkwijk C , et al. Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med 2014; 275 (1) 59-70
  CrossrefPubMedGoogle Scholar
• 106 Stener-Victorin E, Baghaei F, Holm G , et al. Effects of acupuncture and exercise on insulin sensitivity, adipose tissue characteristics, and markers of coagulation and fibrinolysis in women with polycystic ovary syndrome: secondary analyses of a randomized controlled trial. Fertil Steril 2012; 97 (2) 501-508
  CrossrefPubMedGoogle Scholar