Hemostatic and fibrinolytic abnormalities in polycystic ovary syndrome.

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Hemostatic and Fibrinolytic Abnormalities in Polycystic Ovary Syndrome Giovanni Targher, MD1

Giacomo Zoppini, MD1

Enzo Bonora, MD1

1 Section of Endocrinology, Diabetes and Metabolism, Department of

Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy

Paolo Moghetti, MD1

Address for correspondence Giovanni Targher, MD, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata, Piazzale Stefani, 1, 37126 Verona, Italy (e-mail: [email protected]).

Abstract

Keywords

► hemostasis ► polycystic ovary syndrome ► thrombosis

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.

Polycystic ovary syndrome (PCOS), also called Stein– Leventhal syndrome, is a common endocrine disorder that affects a significant proportion of reproductive-age women in the Europe and worldwide. PCOS is one of the leading causes of fertility problems in women, and can lead to additional health problems in later life.1 Many women with PCOS have insulin resistance and additional features of the metabolic syndrome, such as visceral obesity, dyslipidemia, hypertension, or glucose intolerance, all of which may predispose these patients to the development of subclinical and clinical cardiovascular disease.1,2 For several years, the effects of PCOS on coagulation and fibrinolysis have remained largely unexplored. Emerging evidence suggests that PCOS women display abnormalities in coagulation and fibrinolysis pathways. Collectively, PCOS

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

published online July 7, 2014

Issue Theme A Short History of Thrombosis and Hemostasis: Part I (40th Year Celebratory Issue); Guest Editor, Emmanuel J. Favaloro, PhD, FFSc (RCPA).

appears to be associated with a mild to moderate prothrombotic tendency.2,3 Thus, it is conceivable that abnormalities in the coagulation and fibrinolytic systems might contribute to an increased cardiovascular risk in this group of patients.2,3 The purpose of this review is to discuss the epidemiology and diagnosis of PCOS, to update our current knowledge of the connections between PCOS and abnormalities of coagulation and fibrinolysis, and to discuss the putative biological mechanisms linking PCOS to these hemostatic abnormalities. We also discuss some of the treatment options for PCOS that may potentially influence PCOS-associated hemostatic abnormalities.

History, Epidemiology, Diagnosis, and Clinical Phenotypes of PCOS PCOS, as currently defined, is a heterogeneous endocrine disorder characterized by variable degrees of hyperandrogenism and

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DOI http://dx.doi.org/ 10.1055/s-0034-1384512. ISSN 0094-6176.

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Semin Thromb Hemost 2014;40:600–618.

ovarian dysfunction.1 Unfortunately, no feature is universal in these patients, and there are no unequivocal criteria for diagnosis of this syndrome, which requires exclusion of a series of other endocrine disorders, such as late onset congenital adrenal hyperplasia, thyroid dysfunction, hyperprolactinemia, or androgen-secreting tumors. This inconsistency in diagnostic criteria for PCOS may contribute to the heterogeneity of clinical findings in these patients. The first recognized description of PCOS was made in 1935 by two American gynecologists, Stein and Leventhal, who had reported on the association between ovarian polycystic morphology, menstrual dysfunction and obesity, in the presence of frequent hirsutism and infertility.4 However, some clinical descriptions, which might be referable to PCOS were made even at the dawning of medicine, by physicians working in eminent medical schools of the ancient Greece. Around 400 BC, Hippocrates of Cos had observed that women whose menstruation was scarce were often robust and with a masculine appearance, and did not become pregnant.5 Five centuries later, Soranus of Ephesus, one of the most famous physicians of the celebrated Methodic School who practiced medicine in Alexandria and Rome, reported in a treatise of gynecology that lack of menstruation might occur in women, especially in those whose bodies were masculine and robust, and that this alteration was associated with sterility.6 Subsequently, a more structured description of a clinical case with the typical features of PCOS was given in 1721 by the Italian physician Antonio Vallisneri, professor of Theoretical Medicine at the University of Padua. In a textbook on the pathophysiology of reproduction in humans and animals, he first reported on a young overweight woman with infertility, who died accidentally, and who had abnormally large and polycystic ovaries at postmortem examination.7 Currently, according to the conclusions of a joint consensus workshop of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine, held in Rotterdam in 2003,8 PCOS is diagnosed by the presence of at least two of three main features: clinical and/or biochemical hyperandrogenism, chronic oligoanovulation and polycystic ovary morphology, after exclusion of other secondary causes. This definition widened the previous diagnostic criteria of the syndrome, as defined in 1990 by a National Institutes of Health (NIH) consensus conference, which were based only on the coexistence of hyperandrogenism and oligoanovulation and did not include the ovarian morphology.9 The adoption of the Rotterdam diagnostic criteria has had two major consequences: a substantial increase in the prevalence of PCOS from approximately 6 to 8% to 12 to 20%10,11; and a further increase in the clinical heterogeneity of the syndrome. In particular, according to the various possible combinations of the three earlier mentioned diagnostic features that can be observed in each individual PCOS woman, adoption of the Rotterdam criteria have introduced at least three different PCOS phenotypes, subsequently named “classic” (corresponding to previous NIH definition, i.e., presence of hyperandrogenism and oligoanovulation, with or without polycystic ovarian morphology), “ovulatory” (i.e., presence of hyperandrogenism and polycystic ovarian

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morphology), and “normo-androgenic” (i.e., presence of oligoanovulation and polycystic ovarian morphology). In the past decade, the Rotterdam criteria for diagnosing PCOS have been widely used, both in clinical practice and in scientific literature. Nonetheless, the conclusions of the Rotterdam consensus workshop are still being debated. In particular, the Androgen Excess and PCOS (AE-PCOS) Society, while confirming that the diagnosis of PCOS should be based on the three clinical features proposed by the Rotterdam consensus workshop Group, concluded that the presence of hyperandrogenism is always necessary for diagnosing PCOS, combined with oligoanovulation and/or polycystic ovarian morphology.12 In other words, the AEPCOS Society have excluded the possibility of a “normo-androgenic” PCOS phenotype. The discussion on these aspects is still ongoing. Among the consequences of the increased clinical heterogeneity underpinning the use of the Rotterdam diagnostic criteria, an important point is that patients with the various phenotypes of PCOS can substantially differ in terms of coexisting metabolic abnormalities. In particular, although the risk of an adverse metabolic profile is high in PCOS women with the “classic” phenotype, who frequently have insulin resistance and the metabolic syndrome features, it is negligible in those with the “normo-androgenic” phenotype, whereas it is intermediate in those with the “ovulatory” phenotype of the syndrome.13 It is important to underline that obesity, which was a component of the early descriptions of the syndrome, is no longer considered a diagnostic feature of PCOS. However, it is a common finding in these subjects, affecting up to 40 to 60% of them. Moreover, in PCOS women, body fat excess is associated with a worse endocrine, reproductive, and metabolic profile and with more frequent abnormalities suggesting subclinical atherosclerosis.1,2,14 In particular, both hyperandrogenism and insulin resistance are more frequent in obese patients with PCOS. An important implication of these findings is that several clinical abnormalities typical of PCOS women, which are associated with insulin resistance and androgen excess, may be expressed differently in each individual PCOS patient. As a consequence, physicians should be aware that the pharmacological approach to these patients must be personalized, taking into account the specific characteristics of each PCOS patient. Whether or not these differences may also include abnormalities in coagulation and fibrinolysis is still an unexplored issue, although our knowledge of the pathophysiology of hemostasis suggests it could be the case.

Clinical Evidence of Hemostatic and Fibrinolytic Abnormalities in PCOS Review of the literature suggests the presence of mild abnormalities of the hemostatic and fibrinolytic system in PCOS. As detailed later, there is relatively strong evidence indicating that PCOS is associated with increased platelet aggregation and decreased plasma fibrinolytic activity. Collectively, however, it is important to underline that the existing literature is Seminars in Thrombosis & Hemostasis

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limited, with few studies, small sample sizes, and contradicting findings relating to hemostatic parameters in PCOS. Associations of plasma hemostatic factors with hormonal and metabolic parameters in this group of patients also reveal inconsistent findings. Most published studies lack appropriate control groups or did not adjust for important potential confounders, such as visceral adiposity, insulin resistance, and dyslipidemia (especially hypertriglyceridemia). Therefore, this makes the comparison and interpretation of results from published studies very difficult. We believe that further well-conducted case–control and intervention trials on larger series of carefully characterized PCOS patients are needed to better clarify the hemostatic and fibrinolytic abnormalities in PCOS. For the sake of clarity, we will analyze here the results of the principal case–control studies that have explored the abnormalities of coagulation and fibrinolysis in PCOS examining separately the possible effect of PCOS on primary hemostasis (as summarized in ►Table 1),15–27 secondary 2),15,21–23,28–35 fibrinolysis hemostasis (►Table 15,20,24,27–30,33–46 and inhibitors of coagulation (►Table 3), (►Table 4),31–33,35,47–50 respectively. For such reason, a single study that has measured multiple hemostatic parameters could be included in one or more of these tables.

Polycystic Ovary Syndrome and Primary Hemostasis Assessment of primary hemostasis can be undertaken by evaluating its principal components, namely, platelets and the vascular endothelium. The principal case–control studies that have examined the possible effect(s) of PCOS on primary hemostasis are summarized in ►Table 1.15–27

Platelet Number, Volume, and Function Platelet numbers were shown to be significantly higher in women with PCOS compared with those of age- and body mass index (BMI)–matched healthy controls in one study,20 and unchanged in others.16,17,21 Two small case–control studies have demonstrated that mean platelet volume (MPV), that is, a marker of in vivo platelet activation, was significantly higher in nondiabetic PCOS women than in age- and BMI-matched healthy controls.17,21 A significant positive association between MPV and serum androgen levels was observed by Kebapcilar et al,21 but not by Gursoy et al.17 Conversely, Luque-Ramírez et al did not find significant differences in MPV between PCOS women and healthy controls, who were matched for age and BMI.22 Furthermore, increased plasma concentrations of sP-selectin and sCD40 ligand, two other markers of in vivo platelet activation, have been observed in PCOS women compared with healthy controls, who were matched for age, BMI, and waist circumference.18,23 Recently, Koiou et al26 found that the circulating levels of platelet-derived microparticles (i.e., small membrane vesicles released from activated platelets that support coagulation by exposure of anionic phospholipids and tissue factor [TF]) were significantly higher in PCOS women than in matched healthy controls. Moreover, in the PCOS group, these plateletderived microparticles were positively correlated to the number of follicles in the ovaries.26 Seminars in Thrombosis & Hemostasis

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Notably, some experimental studies have also examined platelet aggregation in response to various agonists.16,19,27 Dereli et al found that PCOS women showed an increased platelet aggregation induced by adenosine-5′-diphosphate (ADP), collagen, or epinephrine compared with both control subjects and hyperandrogenic patients with nonclassic congenital hyperplasia.16 Interestingly, there was an inverse association between insulin sensitivity and agonist-induced platelet aggregation in PCOS women, which remained significant after adjustment for serum androgen levels.16 Other investigators found that compared with matched controls, PCOS women also had platelet hyporesponsiveness to the antiaggregatory effect of nitric oxide, irrespective of the obesity status. 19 Recently, however, Kahal et al failed to find significant differences in platelet sensitivity to stimulation with ADP or inhibition with prostacyclin between obese PCOS women and age- and BMI-matched control women.27

Endothelial Function Endothelial function can be assessed indirectly through measurement of its synthesized products: von Willebrand factor (VWF), asymmetric dimethyl-L-arginine (ADMA), and plasminogen activator inhibitor-1 (PAI-1). However, studies on PAI-1 will be analyzed in a specific section later. Several investigators have shown that plasma VWF levels in PCOS women were essentially similar to those of matched healthy controls,15,20,23,24 whereas one study showed that VWF levels were significantly higher in overweight/obese PCOS women than in age- and BMI-matched controls.25 Interestingly, in this latter study, the increase in plasma VWF levels was greater in the subgroup of PCOS women with both hyperandrogenism and anovulation.25 Potential support for endothelial dysfunction in PCOS is largely based on the majority of the observations in the literature that have noted elevated PAI-1 (as detailed later in another section) and ADMA levels in women with PCOS. Most published studies have reported a significant increase in plasma ADMA levels in PCOS women,19,20,51,52 although some investigators failed to find any differences in ADMA levels between PCOS women and controls.53 Interestingly, in the study by Moran et al it has been also reported a significant, positive association between ADMA levels and markers of insulin resistance.20

Polycystic Ovary Syndrome and Secondary Hemostasis Assessment of secondary hemostasis in PCOS can be performed by examining significant coagulation factors within the coagulation pathways. As summarized in ►Table 2, no studies have reported significant differences in prothrombin time, activated partial thromboplastin time, and thrombin time between PCOS women and control subjects.21,22,29,32 Similarly, studies on circulating Factor (F) VII levels in PCOS did not show any significant difference between cases and controls.15,29,31,33 Finally, Yildiez et al did not find significant differences in plasma FII, FV, and FX activities between PCOS women and age- and BMI-matched healthy controls.29


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603

Investigators (y)

Study characteristics

Main study measures

Main findings

Kelly et al (2002)15

Case–control study: 17 obese PCOS women and 15 healthy women matched for BMI

Plasma FVII, fibrinogen, t-PA, D-dimer, and VWF

Only t-PA concentration was significantly (9.8 0.6 vs. 7.7 0.8 ng/mL) elevated in women with PCOS relative to controls. After adjustment for BMI and insulin sensitivity, there remained a significant difference in t-PA concentration between cases and controls

Dereli et al (2003)16

Case–control study: 50 nonobese PCOS women, 50 women with NC-CAH, and 30 healthy controls matched for age, BMI, and waist/hip ratio

Agonist-induced platelet aggregation (epinephrine, ADP, and collagen)

PCOS women displayed a significantly increased platelet aggregation induced by ADP, collagen, and epinephrine, compared with the control group and patients with NC-CAH, respectively. There were significant, inverse, correlations between aggregations induced by agonists and the insulin sensitivity in PCOS women. These correlations remained significant after adjusting for serum androgen levels

Gursoy et al (2006)17

Case–control study: 85 PCOS women and 81 healthy controls matched for age and BMI

MPV

MPV was significantly higher in PCOS women than in controls (8.5 1.4 vs. 7.8 0.9 fl). There was no difference in platelet count between the groups

Oktem et al (2009)18

Case–control study: 31 overweight/obese PCOS women and 31 healthy controls matched for age, BMI, and waist circumference

Plasma sCD40L

Plasma sCD40L levels were significantly higher in PCOS women that in controls (5.1 3.6 vs. 3.5 2.6 ng/mL)

Rajendran et al (2009)19

Case–control study: 24 PCOS women (n ¼ 12 lean and n ¼ 12 obese) and 12 age-matched lean controls

Platelet aggregation and its inhibition by SNP. Plasma MDA, ADMA, and EPC count

In both PCOS subgroups, which demonstrated platelet hyperaggregability to ADP, responses to SNP inhibition of aggregation were significantly impaired, as were their endotheliumdependent vascular responses to salbutamol. However, vasomotor responses to nitroglycerin and circulating EPC counts did not vary between groups. PCOS women also had significantly higher ADMA (0.57 0.01 vs. 0.51 0.01 umol/L) and MDA (0.25 0.02 vs. 0.17 0.02 umol/L) than controls

Moran et al (2009)20

Case–control study: 80 obese PCOS women and 27 healthy controls matched for age, BMI and waist circumference

Plasma PAI-1, VWF, and ADMA

PCOS women had significantly higher ADMA (1.0 0.4 vs. 0.3 0.1 µmol/L) and PAI-1 (5.6 1.8 vs. 4.6 1.1 AU/ mL) levels than controls. For all subjects, ADMA and PAI-1 were increased with higher tertiles of insulin resistance. No significant differences were observed in plasma VWF between the groups

Kebapcilar et al (2009)21

Case–control study: 48 overweight, nondiabetic PCOS women and 30 controls matched for age and BMI

WBC, platelets, MPV, D-dimer, fibrinogen, PT, and APTT

PCOS women had significantly higher D-dimer (206 38.8 vs. 142.7 40.3 ng/mL), MPV (9.4 1.2 vs. 7.4 0.3 fl) and WBC (8.1 1.7 vs. 5.8 1.1) than controls. No significant differences were found in platelet count, fibrinogen, PT, APTT between the groups. In multiple stepwise regression analyses, D-dimer and MPV were positively associated with serum androgens

Luque-Ramírez et al (2009)22

Case–control study: 40 PCOS women (n ¼ 16 obese and

Fibrinogen, PT, APTT, MPV, and platelet count

Test results were similar among PCOS patients and controls with the (Continued)

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Table 1 Principal case–control studies examining the abnormalities of primary hemostasis in PCOS ordered by publication year


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Table 1 (Continued) Investigators (y)


Main study measures

n ¼ 24 nonobese) and 20 healthy controls matched for age and BMI

Main findings exception of a higher platelets count in the PCOS group

Yildiz et al (2010)23

Case–control study: 32 nonobese, nondiabetic PCOS women and 21 healthy controls matched for age, BMI, and waist/hip ratio

Soluble P-selectin and VWF

P-selectin levels were significantly higher in PCOS women than in controls (58.7 19.0 vs. 45.3 15.0 ng/mL). Plasma VWF levels were comparable between the groups

Mannerås-Holm et al (2011)24

Case–control study: 74 overweight, nondiabetic PCOS women and 30 healthy controls

Plasma fibrinogen, D-dimer, VWF, FVIII, t-PA antigen, and PAI-1 activity

PCOS women had significantly higher PAI-1 activity (21.8 24.9 vs. 9.0 10.3 IU/mL) and fibrinogen levels (3.10 0.60 vs. 2.63 0.48 g/L) than controls and the results remained unchanged after adjustment for age and BMI. Differences in PAI-1 activity were not significant after further adjustment for serum androgens and insulin. Plasma levels of D-dimer, VWF, FVIII, t-PA were comparable between the groups

Koiou et al (2012)25

Case–control study: 140 overweight/obese PCOS women and 40 healthy women matched for age and BMI

Plasma VWF

Plasma VWF antigen levels were higher in PCOS women than in controls (57.1 28 vs. 45.9 22%). The increase in VWF levels was greater especially among PCOS women with anovulation and hyperandrogenemia


Case–control study: 67 overweight/obese PCOS women and in 21 healthy women matched for BMI and waist circumference

PMP

Plasma PMP were significantly higher in PCOS women than in controls. In PCOS women, plasma PMPs were positively correlated with the mean number of follicles in the ovaries

Kahal et al (2013)27

Case–control study: 21 obese PCOS women and 19 controls matched for age and BMI

Platelet function (by flow cytometry) and clot structure and fibrinolysis (by turbidimetric assays)

Platelet sensitivity to stimulation with ADP or inhibition with prostacyclin, clot structure and fibrinolytic efficiency ex vivo were not significantly different between the groups

Abbreviations: ADMA, asymmetric dimethyl-L-arginine; ADP, adenosine-5′-diphosphate; APTT, activated partial thromboplastin time; BMI, body mass index; EPC, endothelial progenitor cells; F, factor; MDA, malondialdehyde; MPV, mean platelet volume; NC-CAH, non-classic congenital adrenal hyperplasia; PAI-1, plasminogen activator inhibitor-1; PCOS, polycystic ovary syndrome; PMP, platelet-derived microparticles; PT, prothrombin time; sCD40L, soluble CD40 ligand; SNP, sodium nitroprusside; t-PA, tissue plasminogen activator; VWF, von Willebrand factor; WBC, white blood count.

Studies on plasma levels of fibrinogen in PCOS have yielded conflicting results. Indeed, plasma fibrinogen levels in PCOS women were observed to be similar to15,21,22,29,32 or higher than24,28 those of matched healthy controls. No correlation was found between plasma androgens and fibrinogen levels in PCOS.21 Plasma levels of D-dimer, as a marker of fibrin formation and degradation, have been shown to be significantly elevated in PCOS women21,33 or unchanged15,24,29,32 compared with those in healthy controls. Interestingly, Kebapcilar et al also found a significant, positive correlation between plasma D-dimer and free testosterone levels in PCOS women.21 Where elevated D-dimer levels occur in PCOS, these are likely to represent increased subclinical fibrin generation, rather than elevated fibrin degradation, because global fibrinolytic capacity is reduced. More recently, a single study that has measured plasma TF levels found that PCOS women had significantly higher Seminars in Thrombosis & Hemostasis

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plasma TF levels than matched healthy controls, independently of obesity status.34 Thrombin generation (TG) is a recently reinvigorated global coagulation test that measures the interaction capacity between all the plasmatic hemostatic components that result in the formation of the fibrin clot. For this reason, it is considered a good indicator of secondary hemostasis. Recently, de Mendonça-Louzeiro et al 35 compared 45 young and overweight women with PCOS and 45 women of the same age, BMI, and waist circumference, who did not have PCOS. Notably, they found that among the hemostatic markers evaluated, the only statistically significant difference between the groups was in TG lag-time. Therefore, in PCOS women, the time until the initial thrombin burst was significantly shorter compared with matched controls, showing that in this group of patients TG is faster (thus suggesting a greater risk of hypercoagulability).35


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605

Investigators (y)


Main study measures

Main findings

Atiomo et al (1998)28

Case–control study: 11 overweight/obese PCOS women and 12 nonobese controls

Euglobulin clot lysis time, plasma PAI-1 activity, fibrinogen, plasminogen, and antiplasmin

PCOS women had a significantly longer euglobulin clot lysis time (389 164 vs. 220 110 minutes), a higher PAI-1 activity (19.7 12 vs. 10.9 7.9 AU/mL), and a higher fibrinogen level (4.02 0.64 g/L vs. 3.15 0.6 g/L) compared with controls


Case–control study: 59 nonobese, normal glucose-tolerant PCOS women and 23 healthy controls matched for age and BMI

GFC, PT, APTT, thrombin time, AT-III, fibrinogen, F II, FV, FVII, and FX; plasminogen, antiplasmin, and D-dimer

GFC was significantly lower in PCOS women than in controls (2.5 1.6 vs. 5.9 2.4 ug/mL). No significant differences were found in all other coagulation parameters between the groups. GFC was inversely correlated with serum testosterone and free testosterone levels. No significant correlation was found between GFC and insulin resistance


Case–control study: 17 obese women with PCOS and 15 healthy women matched for BMI

Plasma FVII, fibrinogen, t-PA, Ddimer, and VWF


Słopień et al (2006)30

Case–control study: 19 obese women with PCOS and 81 healthy controls matched for age and BMI

Euglobulin clot lysis time, plasminogen, antiplasmin, PAI-1 activity, and fibrinogen

All of the hemostatic-fibrinolytic parameters with the exception of plasminogen were comparable between the groups. Plasminogen level was lower in PCOS women than in controls

Erdoğan et al (2008)31

Case–control study: 68 nonobese PCOS women and 26 healthy controls matched for age and BMI

Plasma fibrinogen and TAFI

No significant differences were found in plasma fibrinogen and TAFI levels between the groups

Karakurt et al (2008)32

Case–control study: 42 nonobese women with PCOS and 30 age-matched healthy controls

Plasma TAFI, fibrinogen, D-dimer, PT, and APTT

PCOS women had significantly higher levels of TAFI (125.3 41 vs. 75.8 25%). Other hemostatic parameters were comparable between the groups

Oral et al (2009)33


Plasma TAFI, PAI-1, fibrinogen, thrombomodulin, thrombin–antithrombin complexes, D-dimer, protein C, protein S, AT-III, and APC resistance

PCOS women had significantly higher plasma levels of TAFI (93.8 31 vs. 79.8 22%), D-dimer (280.6 69 vs. 227.6 74 ng/mL), AT III (74.4 20 vs. 50.6 18%), PAI-1 (70.3 59 vs. 45.6 36.9 ng/mL) and thrombomodulin (3.2 0.8 vs. 2.6 0.9 ng/mL) compared with controls. Other hemostatic parameters did not differ between the groups

Kebapcilar et al (2009)21

Case–control study: 48 overweight, nondiabetic PCOS women and 30 controls matched for age and BMI

WBC, platelet count, MPV, D-dimer, fibrinogen, PT, and APTT

PCOS women had significantly higher Ddimer (206 38.8 vs. 142.7 40.3 ng/ mL), MPV (9.4 1.2 vs. 7.4 0.3 fl), and WBC (8.1 1.7 vs. 5.8 1.1) than controls. No significant differences were found in platelet count, fibrinogen, PT, APTT between the groups. In multiple stepwise regression analyses, D-dimer and MPV were positively associated with serum androgens (Continued)


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Table 2 Principal case–control studies examining the abnormalities of secondary hemostasis in PCOS ordered by publication year


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Main study measures

Main findings

Luque-Ramírez et al (2009)22

Case–control study: 40 PCOS women (n ¼ 16 obese and 24 nonobese) and 20 healthy controls matched for age and BMI

Fibrinogen, PT, APTT, MPV, and platelet count

Blood clotting tests were similar among PCOS patients and controls with the exception of a higher platelets count in the PCOS group




PCOS women had significantly higher PAI1 activity (21.8 24.9 vs. 9.0 10.3 IU/ mL) and fibrinogen levels (3.10 0.60 vs. 2.63 0.48 g/L) than controls and the results remained unchanged after adjustments for age and BMI. Differences in PAI-1 activity were not significant after further adjustment for serum androgens and insulin. Plasma levels of D-dimer, VWF, FVIII, and t-PA were comparable between the groups

González et al (2013)34

Case–control study: 12 PCOS women (n ¼ 6 lean and n ¼ 6 obese) and 12 controls matched for age and BMI

Plasma TF and PAI-1 antigen

Circulating TF levels are elevated in PCOS, independently of obesity status. PAI-1 levels were higher only in lean PCOS women compared with those in lean controls

de MendonçaLouzeiro et al (2013)35

Case–control study: 45 overweight/obese PCOS women and in 45 healthy women matched for age, BMI and waist circumference

TG, and plasma TAFI, D-dimer, and PAI-1

TG was significantly faster in PCOS women than in controls. No significant differences were found in other plasma hemostatic parameters between the groups

Abbreviations: APC resistance activated protein C; APTT , activated partial thromboplastin time; AT-III, antithrombin III; BMI, body mass index; F, factor; GFC, global fibrinolytic capacity; MPV, mean platelet volume; PAI-1, plasminogen activator inhibitor-1; PCOS, polycystic ovary syndrome; PT, prothrombin time; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; t-PA, tissue plasminogen activator; VWF, von Willebrand factor; WBC, white blood count.

Polycystic Ovary Syndrome, Fibrinolysis, and Other Inhibitors of Coagulation The fibrinolytic system and other inhibitors of coagulation act to control the prothrombotic effects of markers of the secondary hemostatic system. The principal case–control studies that have examined the possible effects of PCOS on fibrinolysis and other inhibitors of coagulation are summarized in ►Table 3 15,20,24,27–30,33–46 and ►Table 4.31–33,35,47–50

Protein C, Activated Protein C, Protein S, Antithrombin and Thrombomodulin Plasma antithrombin levels in women with PCOS are either similar to29,50 or higher33 than those of age- and BMImatched healthy controls. Protein C, protein S, and prevalence of activated protein C resistance have been shown to be comparable to those of age- and BMI-matched controls.33,47,48 Only a single study, involving a relatively large series of nonobese women with a history of recurrent pregnancy loss, found that the prevalence of protein C deficiency was greater among those with PCOS than among their counterparts without the syndrome.50 Finally, Oral et al reported that plasma thrombomodulin levels were significantly higher in nonobese PCOS women than in age- and BMI-matched controls.33 However, it is important to note that the relationships of all these hemoSeminars in Thrombosis & Hemostasis

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static parameters with metabolic or hormonal variables in PCOS have not been explored.

Plasminogen Although a significant component of the fibrinolytic system, only three small case–control studies have been published assessing plasma plasminogen levels in PCOS—two showing similar28,29 and the other showing significantly lower levels of plasminogen activity in lean or obese women with PCOS compared with age- and BMI-matched healthy controls.30

Tissue Plasminogen Activator Plasma tissue plasminogen activator (t-PA) levels have been shown to be either similar to24,41 or higher15,42,45 than those in matched healthy controls. Interestingly, in the study by Kelly et al the difference in plasma t-PA levels between PCOS women and controls remained statistically different even after adjustment for insulin sensitivity.15 Conversely, no significant correlations between plasma t-PA and testosterone levels were observed in any published studies.15,42

Plasminogen Activator Inhibitor-1 As summarized in ►Table 3, several studies have consistently shown that the level and/or activity of PAI-1 is significantly


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Investigators (y)


Main study measures

Main findings

Sampson et al (1996)

Case–control study: 24 nonobese PCOS women with extreme menstrual disturbances (group 1), 26 age-, BMI-matched controls with normal menstrual cycle and ultrasound appearance of PCOS (group 2) and 10 matched controls with normal menstrual cycle and normal ovarian ultrasound (group 3)

Plasma PAI-1 activity

Plasma PAI-1 activity levels were significantly higher in group 1 (10.0 7.1 AU/ L) than in group 2 (6.0 4.6 AU/L) or group 3 (5.1 3.5 AU/L). There was a positive, independent, association between fasting plasma insulin and PAI-1 activity levels


Case-control study: 11 overweight/obese PCOS women and 12 nonobese controls

Euglobulin clot lysis time, plasma PAI-1 activity, fibrinogen, plasminogen, and antiplasmin

PCOS women had a significantly longer euglobulin clot lysis time (389 164 vs. 220 110 minutes), a higher PAI-1 activity (19.7 12 vs. 10.9 7.9 AU/mL), and a higher fibrinogen level (4.02 0.64 g/L vs. 3.15 0.6 g/L) compared with controls


Case–control study: 41 overweight PCOS women and 25 controls matched for BMI and waist circumference


29% of PCOS women had a positive family history of thrombosis compared with 8% in the control group. There was no significant difference in PAI-1 activity levels between the two groups


Case–control study: 59 nonobese, normal glucosetolerant PCOS women and 23 healthy controls matched for age and BMI

GFC, PT, APTT, thrombin time, AT-III, fibrinogen, FII, FV, FVII, and FX; plasminogen, antiplasmin, and D-dimer

GFC was significantly lower in PCOS women than in controls (2.5 1.6 vs. 5.9 2.4 ug/mL). No significant differences were found in all other coagulation parameters between the groups. GFC was inversely correlated with serum testosterone and free testosterone levels. No significant correlation was found between GFC and insulin resistance


Case–control study: 17 obese PCOS women and 15 healthy women matched for BMI

Plasma FVII, fibrinogen, t-PA, D-dimer, and VWF


Tarkun et al (2004)38

Case–control study: 32 nonobese PCOS women and 25 healthy controls matched for age, BMI, and waist circumference

Plasma PAI-1 antigen and activity

PAI-1 antigen and activity were significantly higher in PCOS women than in controls (34.1 15.0 vs. 24.6 14.1 ng/mL and 12.8 3.1 vs. 5.6 2.1 U/mL, respectively). PAI-1 levels were positively correlated with insulin resistance markers

Diamanti-Kandarakis et al (2004)39

Case–control study: 98 nonobese PCOS patients and 64 controls matched for age and BMI

Plasma PAI-1 and 4G/5G polymorphism of PAI-1 gene

PCOS women had significantly higher 4G/4G and 4G/5G genotype polymorphism combinations than controls. PCOS women also had significantly higher PAI-1 levels (72.3 5.1 vs. 48.9 6.3 ng/mL) than controls

Orio et al (2004)40

Case–control study: 30 PCOS women (n ¼ 15 lean and n ¼ 15 obese) and 30 healthy controls matched for age and BMI


PCOS women had significantly elevated PAI-1 activity, independently of obesity status

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Main study measures

Main findings

Carmassi et al (2005)41

Case–control study: 64 lean and obese PCOS patients (19 insulin-resistant and 45 insulin-sensitive) and 25 healthy controls matched for age

PAI-1 and t-PA antigen levels measured during insulin infusion into the forearm

Elevated basal PAI-1 levels were found in PCOS women (93.1 45.1 fmol/mL in insulin-resistant PCOS vs. 57.8 38.4 fmol/mL in insulin-sensitive PCOS vs. 41.4 17.8 fmol/mL in controls, p < 0.05 for all groups), correlating positively with insulin levels. PAI-1 expression increased during insulin infusion in all PCOS women, but was delayed and sustained in insulinresistant patients. Vasodilatory response to insulin was blunted and t-PA expression abolished in insulin-resistant PCOS patients

Słopień et al (2006)30

Case–control study: 19 obese PCOS women and 81 healthy controls matched for age and BMI

Euglobulin clot lysis time, plasminogen, antiplasmin, PAI-1 activity, and fibrinogen

All of the hemostatic–fibrinolytic parameters, with the exception of plasminogen, were comparable between the groups. Plasminogen level was lower in PCOS women than in controls

Lin et al (2008)42


Plasma PAI-1, t-PA, and uPA

PCOS women had significantly higher levels of PAI-1 (67.6 21.2 vs. 54.3 19.4 ng/mL) and t-PA (12.1 2.7 vs. 9.8 2.1 ng/mL). Levels of u-PA tended to be higher (0.76 0.2 vs. 0.69 0.2 ng/mL)

Oral et al (2009)33


Plasma TAFI, PAI-1, fibrinogen, thrombomodulin, thrombin–antithrombin complexes, D-dimer, protein C, protein S, AT-III, and APC resistance

PCOS women had significantly higher plasma TAFI (93.8 30.6 vs. 79.8 22.4%), D-dimer (280.6 69.4 vs. 227.6 73.9 ng/mL), AT III (74.4 20.0 vs. 50.6 17.8%), PAI-1 (70.3 59 vs. 45.6 36.9 ng/mL) and thrombomodulin (3.2 0.8 vs. 2.6 0.9 ng/mL) levels compared with controls. Other hemostatic parameters did not differ between the groups

Moran et al (2009)20

Case–control study: 80 obese PCOS women and 27 healthy controls matched for age, BMI, and waist circumference

Plasma PAI-1, VWF, and ADMA

PCOS women had significantly higher plasma ADMA (1.0 0.4 vs. 0.3 0.1 µmol/L) and PAI-1 (5.6 1.8 vs. 4.6 1.1 AU/mL) levels than controls. For all subjects, ADMA and PAI-1 levels were increased with higher tertiles of insulin resistance. No significant differences were observed in plasma VWF between the groups

Lin et al (2009)43

Case–control study: 126 nonobese PCOS women and 21 healthy controls matched for age and waist/hip ratio

PAI-1 gene polymorphism and plasma PAI-1 antigen

A trend to a positive interaction between PAI-1 675 4G/5G and 844 A/G gene polymorphism may elevate plasma PAI-1 levels in PCOS women

Gonzalez et al (2009)44

Case–control study: 16 PCOS women (n ¼ 8 lean and n ¼ 8 obese) and 16 weight-matched controls

Plasma PAI-1 and endothelial adhesion molecules

Trend analysis revealed significantly higher PAI-1, sICAM-1, monocyte chemotactic protein-1 and other plasma inflammatory markers in PCOS women compared with BMI-matched controls, and the highest levels in obese subjects, regardless of PCOS status

Lindholm et al (2010)45

Case–control study: 135 PCOS women (lean and obese) and

Plasma PAI-1 and t-PA activity and antigen

Obese PCOS women had significantly higher t-PA antigen (8.9 3.6 vs. 7.8 3.1 ng/mL) and PAI-1 activity


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Table 3 (Continued) Study characteristics

Main study measures

Main findings (20.7 19.5 vs. 13.0 13.8 IU/mL) than controls. Lean PCOS women did not differ in terms of PAI-1 activity or t-PA mass concentration in comparison to controls

81 healthy controls matched for BMI and waist/hip ratio




PCOS women had significantly higher PAI-1 activity (21.8 24.9 vs. 9.0 10.3 IU/mL) and fibrinogen levels (3.1 0.60 vs. 2.6 0.50 g/L) than controls, and the results remained unchanged after adjustments for age and BMI. Differences in PAI-1 activity were not significant after further adjustment for serum androgens and insulin. Plasma D-dimer, VWF, FVIII, and t-PA levels were comparable between the groups


Case–control study: 199 overweight/obese PCOS women and 50 age- and BMI-matched healthy women

Plasma PAI-1

Plasma PAI-1 antigen levels were higher in overweight/obese PCOS women but not in normal weight women with this syndrome. Plasma PAI-1 levels did not differ between the different phenotypes of PCOS


Case–control study: 45 overweight/obese PCOS women and in 45 healthy women matched for age, BMI, and waist circumference

TG, plasma TAFI, D-dimer, and PAI-1


González et al (2013)34

Case–control study: 12 PCOS women (n ¼ 6 lean and n ¼ 6 obese) and 12 controls matched for age and BMI

Plasma TF and PAI-1 antigen

Circulating TF levels are elevated in PCOS, independent of obesity status. PAI-1 levels were higher only in lean PCOS women compared with those in lean controls

Kahal et al (2013)27

Case–control study: 21 obese PCOS women and 19 healthy controls matched for age and BMI

Platelet function (by flow cytometry), clot structure and fibrinolysis (by turbidimetric assays)

Platelet sensitivity to stimulation with ADP or inhibition with prostacyclin, clot structure and fibrinolytic efficiency ex vivo were not significantly different between the groups

Abbreviations: ADMA, asymmetric dimethyl-L-arginine; ADP, adenosine-5′-diphosphate; APC resistance, activated protein C; APTT , activated partial thromboplastin time; AT-III, antithrombin III; BMI, body mass index; F, factor; GFC, global fibrinolytic capacity; PCOS, polycystic ovary syndrome; PAI-1, plasminogen activator inhibitor-1; PT, prothrombin time; sICAM-1, soluble intercellular adhesion molecule-1; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; TG, thrombin generation; t-PA, tissue plasminogen activator; u-PA, urokinase plasminogen activator; VWF, von Willebrand factor.

higher among PCOS women than among matched healthy controls,24,28,36,38,44–46 although some investigators did not observe any significant difference in PAI-1 levels between cases and controls.30,35,37,46 Notably, a significant positive association between PAI-1 levels and insulin resistance in PCOS has been observed in most of the published studies,20,36,38,41 with only few noting the contrary.40 In addition, in some of the published studies, a strong interaction was found between PAI-1 gene 4G/ 5G gene polymorphism and PAI-1 levels.39,43 Presently, it remains still uncertain if PAI-1 levels correlate with serum androgen levels. In this regard, one study found a significant positive association,24 whereas another did not.46

Antiplasmin and Thrombin Activatable Fibrinolysis Inhibitor Few small case–control studies have measured the circulating levels of antiplasmin and thrombin activatable fibrinolysis inhibitor (TAFI) levels in PCOS. Collectively, no significant differences were found in antiplasmin levels between PCOS women and healthy controls.28–30 Conversely, plasma TAFI levels have been shown to be elevated32,33,50 or similar to those in age- and BMI-matched healthy controls.31,35 A significant, positive association was also observed between plasma TAFI levels and markers of insulin resistance in one study,33 but not in another.31 Seminars in Thrombosis & Hemostasis

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Investigators (y)


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Table 4 Principal case–control studies examining the abnormalities of coagulation-fibrinolytic inhibitors in PCOS ordered by publication year Investigators (y)


Main study measures

Main findings


Case–control study: 41 overweight PCOS women and 25 controls matched for BMI and waist circumference

APC resistance, AT-III, protein C, and protein S

29% of PCOS women had a positive family history of thrombosis compared with 8% in the control group. There were no significant differences in the proportion of those with APC resistance or in other hemostatic factors between the groups

Tsanadis et al (2002)48


Protein C, protein S, AT-III, factor V Leiden, prothrombin G20210A factor

There was no evidence that the genetic analysis for factor V Leiden or prothrombin factor differed between the two groups. Median proportion of activated protein C, protein S, AT-III, and activated protein C ratios were also comparable in both the groups

Erdoğan et al (2008)31


Plasma fibrinogen and TAFI

No significant differences were found in plasma fibrinogen and TAFI levels between the groups

Karakurt et al (2008)32

Case–control study: 42 nonobese PCOS women and 30 age-matched healthy controls

Plasma TAFI, fibrinogen, D-dimer, PT, and PTT

PCOS women had significantly higher levels of TAFI (125.3 41 vs. 75.8 25%). Other plasma hemostatic parameters were comparable between the groups

Oral et al (2009)33


Plasma TAFI, PAI-1, fibrinogen, thrombomodulin, thrombin–antithrombin complexes, D-dimer, protein C, protein S, AT-III, APC resistance

PCOS women had significantly higher plasma levels of TAFI (93.8 30.6 vs. 79.8 22.4%), D-dimer (280.6 69.4 vs. 227.6 73.9 ng/ mL), AT III (74.4 20.0 vs. 50.6 17.8%), PAI-1 (70.3 59 vs. 45.6 36.9 ng/mL) and thrombomodulin (3.2 0.8 vs. 2.6 0.9 ng/ mL) compared with controls. Other hemostatic parameters did not differ between the groups

Adali et al (2010)49

Case–control study: 40 PCOS women (n ¼ 26 nonobese and n ¼ 14 overweight or obese) and 25 healthy controls matched for age

Plasma TAFI

Plasma TAFI levels were significantly higher in the overweight/obese PCOS group than those in the nonobese PCOS and control groups

Moini et al (2012)50

Case–control study: 92 nonobese PCOS women and 92 patients without PCOS matched for age and BMI (all the recruited patients had a history of recurrent pregnancy loss)

Plasma protein S, protein C, factor V Leiden, AT-III activity, antiphospholipid antibodies

The prevalence of protein C deficiency was higher in PCOS women than in controls (21.7 vs. 10.9%). There was a trend toward higher prevalence of protein S deficiency in the PCOS group compared with the control group, but the difference did not reach statistical significance (23.9 vs. 13%). The prevalence of other thrombotic disorders was comparable between the groups


Case–control study: 45 overweight/obese PCOS women and in 45 healthy women matched for age, BMI, and waist circumference

TG and plasma TAFI, D-dimer, PAI-1


Abbreviations: APC resistance, activated protein C; APTT , activated partial thromboplastin time; AT-III, antithrombin III; BMI, body mass index; PAI-1, plasminogen activator inhibitor-1; PCOS, polycystic ovary syndrome; PT, prothrombin time; TAFI, thrombin activatable fibrinolysis inhibitor; TG, thrombin generation.


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Fig. 1 Schematic representation of the putative mechanisms linking PCOS to abnormalities of coagulation and fibrinolysis. NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome.

Euglobin Clot Lysis Time and Global Fibrinolytic Capacity Euglobin clot lysis time (ECLT) and global fibrinolytic capacity (GFC) are thought to be superior assays for identifying fibrinolytic potential rather than examining individual plasma fibrinolytic components.27–29 Assessment of the overall fibrinolytic system would identify the net hemostatic effect. Atiomo et al found that overweight or obese women with PCOS had a significantly longer ECLT than nonobese controls,28 whereas other investigators did not find any significant differences in ECLT between women with PCOS and ageand BMI-matched healthy controls.27,30 Recently, in a study involving 59 nonobese, normal glucose-tolerant women with PCOS and 23 healthy women matched for age and BMI, Yildiz et al found that GFC was significantly lower in PCOS women. Interestingly, these authors also found that GFC was inversely associated with serum testosterone levels but not with markers of insulin resistance.29

between PCOS and prothrombotic state are multifactorial, involving both acquired and hereditary factors, often overlapping with the metabolic disorders that frequently coexist in PCOS, such as visceral obesity, insulin resistance, dyslipidemia, and dysglycemia.1,3,54 As shown in the schematic ►Fig. 1, the putative underlying mechanisms that link PCOS to hemostatic–fibrinolytic abnormalities probably have their origin in the expanded and inflamed visceral adipose tissue, with the liver being both the target of the resulting systemic abnormalities and an important source of several prothrombotic mediators that may further amplify vascular damage. However, further research is needed to uncover additional specific mechanisms by which PCOS may contribute to the development of hemostatic and fibrinolytic abnormalities. In the following paragraphs, we briefly discuss the main factors (or determinants), which are potentially involved in the pathophysiology of hemostatic and fibrinolytic abnormalities seen among women with PCOS.

Putative Mechanisms Linking PCOS to Hemostatic and Fibrinolytic Abnormalities

Factors that May Alter Coagulation and Fibrinolysis in PCOS

Although the pathogenic mechanisms linking PCOS to abnormalities of coagulation and fibrinolysis are not fully understood, understanding the potential pathways between these pathologic conditions may be important as this might lead to new therapeutic strategies of PCOS and its related hemostatic disorders. The tight interrelationships of PCOS with visceral obesity, insulin resistance, and androgen excess make it challenging to identify the main causal factor(s) that underlies the prothrombotic state seen among patients with PCOS. It is plausible to assume that the mechanisms underlying the association

Chronic Inflammation Elevated concentrations of plasma inflammatory biomarkers in women with PCOS have led to hypothesize that this syndrome is associated with a low-grade, chronic inflammatory state.1–3,55 It is known that plasma proinflammatory biomarkers may predict the development of future cardiovascular events, and are closely associated with increased levels of multiple hemostatic and fibrinolytic factors.56,57 In particular, PCOS women have elevated plasma levels of C-reactive protein as compared with healthy controls, although this difference Seminars in Thrombosis & Hemostasis

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may disappear after adjustment for age and BMI.24 Nonetheless, a recent meta-analysis demonstrated that both lean and obese patients with PCOS have increased plasma C-reactive protein levels compared with BMI-matched controls, indicating that the subclinical inflammation seen in PCOS might be mainly related with the presence of the disorder rather than with obesity.58 Thus, subclinical inflammation is thought to be an important underlying mechanism leading to coagulation/ fibrinolysis abnormalities in PCOS. However, the specific role played by obesity deserves further studies. Others plasma inflammatory biomarkers, such as interleukin 6 and tumor necrosis factor α, have been studied in PCOS women, but none of these proinflammatory biomarkers were found to be higher in PCOS women than in matched controls.24,58,59

Dyslipidemia Lipid abnormalities may activate platelet adhesion, coagulation pathway, and inhibit fibrinolysis.60,61 Several case– control studies have shown that, compared with controls, women with PCOS have an atherogenic lipid profile that is typically characterized by increased triglycerides and decreased high-density lipoproteins–cholesterol levels.24,62,63 Plasma total cholesterol and low-density lipoproteins–cholesterol levels do not differ in PCOS women compared with controls.64 Experimentally, it has been demonstrated that plasma triglycerides and their constituents (fatty acids) can increase the expression of PAI-1 in HepG2 cells, and that the combination of elevated triglyceride and insulin levels can exert a synergistic increase in PAI-1 accumulation in the conditioned media of such cells.65

Nonalcoholic Fatty Liver Disease Like PCOS, nonalcoholic fatty liver disease (NAFLD) has a strong association with the metabolic syndrome, obesity, and insulin resistance.66 NAFLD is increasingly diagnosed worldwide and is associated with an increased risk of cardiovascular disease.66,67 It is conceivable that the increased risk of cardiovascular disease observed in NAFLD patients is, at least in part, mediated by increased levels of multiple prothrombotic factors.66,67 Increasing evidence suggests that NAFLD may exacerbate systemic and hepatic insulin resistance, cause atherogenic dyslipidemia, and release a variety of proinflammatory (e.g., C-reactive protein and interleukin 6) and procoagulant (e.g., fibrinogen and PAI-1) mediators that may play important roles in the development of cardiovascular disease.68,69 Notably, the prevalence of NAFLD on ultrasonography in PCOS women has been reported to be as high as 40 to 60%.70,71 Recently, Jones et al found that PCOS with hyperandrogenism is characterized by an increased risk of NAFLD, as detected by proton magnetic resonance spectroscopy, compared with nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. 72 Collectively, all these observations suggest that PCOS women should be routinely screened for NAFLD.70,71 In addition, it is plausible to assume that some alterations of coagulation and fibrinolysis seen in PCOS women are likely because of the coexisting NAFLD. Seminars in Thrombosis & Hemostasis

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Visceral Obesity and Insulin Resistance Visceral obesity is a major feature of PCOS, being present in at least 50 to 60% of these women.1,2,73 Some experimental data suggest that the maturation of adipocytes and visceral obesity may also be favored by chronic hyperandrogenemia, which typically characterizes PCOS.1,74 It is well established that visceral obesity is closely associated with chronic inflammation and insulin resistance.75 Both these conditions may increase the synthesis of PAI-1 by adipocytes.76 As discussed earlier, insulin resistance is a common feature in PCOS (being present in 65–70% of women with PCOS) and may occur independently of obesity. 1 It is well established that insulin resistance/hyperinsulinemia may alter fibrinolysis by enhancing PAI-1 secretion.76,77 Moreover, it has been shown that hyperinsulinemia can also inhibit the hepatic production of sex hormone binding globulin (SHBG).78 Both low SHBG and high insulin levels are strong predictors of elevated PAI-1 activity levels in PCOS women.24 However, as mentioned earlier, the complex and intertwined interactions between PCOS, visceral obesity, insulin resistance, and chronic inflammation make it extremely difficult to dissect out the precise causal relationships responsible for the prothrombotic abnormalities observed in PCOS women.

Androgen Excess Clinical and/or biochemical hyperandrogenism is considered a key feature in PCOS.1,79 However, in PCOS hyperandrogenism often coexists with insulin resistance and the interactions of these two conditions with the hemostatic–fibrinolytic systems are very complex and not completely understood. Moreover, even though the individual contributions of hyperandrogenism and insulin resistance to coagulation and fibrinolysis abnormalities in PCOS women are intensely under evaluation, the exact mechanisms remain speculative. Some small studies have shown a significant association between decreased plasma fibrinolytic activity and high circulating levels of androgens in PCOS women.29,40 Interestingly, an experimental model of transgenic female mice that constitutively expressed a stable variant of human PAI-1 suggested that an inappropriate elevation in PAI-1 concentrations may contribute to the development of polycystic ovarian structures.80 In particular, in this experimental model, the authors have characterized the phenotypic alterations in ovaries from transgenic female mice constitutively expressing a stable form of human PAI-1, and determined plasma testosterone levels in these mice as opposed to their unaffected counterparts. Notably, over half of the ovaries from transgenic mice contained large cystic structures in contrast to wild-type control mice with the same genetic background. Moreover, plasma testosterone levels were nearly twofold higher in transgenic female mice than in wild-type female mice.80 Thus, these findings may reorient the efforts aimed at the development of new therapeutic agents for the treatment of PCOS.80 Hyperandrogenemia may lead to excessive early follicular growth, which then impairs follicular development as well as


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the selection and ovulation of a dominant follicle. These changes may contribute to the loss of both the dynamic architecture of the ovary and the regression (or atresia) of follicles. The resulting hypertrophied theca (interstitium) of the ovary prompts a deleterious feedback loop, which may perpetuate increased testosterone production.81 Treatment with insulin sensitizers is associated with a reduction in PAI-1 levels that is also paralleled by a decline in circulating androgen levels, suggesting a link between plasma androgens and PAI-1 levels.82 Very few studies have found a relationship between hyperandrogenism and plasma levels of fibrinogen or other coagulation factors in PCOS.83 More research is required to better clarify the impact of hyperandrogenism per se on coagulation and fibrinolysis in PCOS.

PCOS Treatment and Its Possible Impact on Hemostasis and Fibrinolysis As the underlying pathophysiology of PCOS is largely unknown, the current therapeutic approach to these patients is to a large extent symptomatic. When the objective is to counteract the clinical signs of androgen excess, such as hirsutism or acne, there is substantial consensus about a strategy based on hormonal contraception as a first-line therapy, and antiandrogen medications as a second-line therapy, associated with several cosmetic procedures.14,84 However, in the absence of specific contraindications, management of clinically important hirsutism usually requires a combined and prolonged pharmacological treatment with hormonal contraceptives and antiandrogens. This strategy is aimed at reducing both androgen levels and androgen action, while ensuring reliable contraception —which is required when antiandrogens are given to women of reproductive age. The choice of a specific hormonal preparation for these patients is more controversial. The Endocrine Society does not suggest any specific formulation over another, as available literature is extremely limited in terms of comparison of efficacy between different hormonal contraceptives.14 Conversely, the AE-PCOS Society recommends preferring low-dose oral contraceptives containing a neutral progestin, such as desogestrel or gestodene, or an antiandrogen molecule, such as cyproterone acetate, chlormadinone acetate, or the spironolactonederivative drospirenone.84 In anovulatory PCOS women seeking immediate fertility, the pharmacological approach includes the antiestrogen clomiphene citrate, gonadotropins (or laparoscopic ovarian drilling), and in vitro fertilization, as first-line, second-line, and third-line therapeutic strategies, respectively.85 However, a combined hormonal contraceptive is usually prescribed when the objective is to guarantee regular menstrual bleeding in patients presenting with menstrual dysfunction, while preventing the risk of endometrial hyperplasia.14,84 An alternative pharmacological approach to PCOS, aimed at improving both the reproductive and the metabolic alterations, is represented by the insulin sensitizer

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metformin. Several studies have consistently shown that metformin may improve not only the metabolic abnormalities but also the ovulation rate in approximately 50% of patients with PCOS.86 Although a head-to-head comparison between this drug and clomiphene citrate (i.e., a selective estrogen receptor modulator that is the most widely prescribed drug for ovulation induction) showed that the latter is better in terms of both ovulation induction and live birth ratio,87 metformin appears a unique option when the aim is not a pregnancy but to steadily resume ovulatory function over time.88 The mechanisms of action of metformin are only partially understood and include inhibition of mitochondrial complex I, accumulation of adenosine monophosphate (AMP) with stimulation of the AMPdependent protein kinase and inhibition of adenylate cyclase, and inhibition of mammalian target of rapamycin mTOR signaling. Metformin likely plays its role in improving ovulation induction in PCOS women through a variety of actions, including reducing insulin levels and altering the effect of insulin on ovarian androgen biosynthesis, theca cell proliferation, and endometrial growth.88,89 To date, however, our knowledge about the potential impact of these different treatments on hemostasis and fibrinolysis in PCOS is very limited. Notably, it is usually accepted that PCOS may be associated with an increased cardiovascular risk. However, this opinion is mainly based on surrogate indices of cardiovascular risk, and no large prospective studies definitely support this conclusion.90 To date, there is evidence from large population-based studies that hormonal contraception is associated with an increased risk of both arterial and venous thrombosis in the general adult population, although this risk is usually mild in the absence of specific risk factors.91–94 Moreover, there is also emerging evidence that such thrombotic risk may differ according to specific hormonal preparations. In particular, some data suggest that the risk for myocardial infarction may be higher with second generation oral contraceptives,91 whereas the risk of venous thromboembolism may be higher with third generation contraceptives.95 It is noteworthy that a relative increase in the risk of venous thromboembolism was also reported in women using contraceptives containing antiandrogens, such as cyproterone acetate or drospirenone,96–99 which are widely used in PCOS women. Nonetheless, there are insufficient data to answer the question as to whether PCOS women face increased risk of either myocardial infarction or venous thromboembolism on specific hormonal contraceptives. A large study performed within a population of women with acne, hirsutism, or PCOS, confirmed that the risk of venous thromboembolism may be higher in women taking preparations containing cyproterone acetate than in those receiving conventional oral contraceptives.100 However, these populations may differ in terms of disease severity. Moreover, although these women may potentially be at increased risk of cardiovascular and thromboembolic events, we cannot rule out the possibility that attenuation of hyperandrogenism by hormonal contraception may exert some favorable effects on these aspects. In this regard, Seminars in Thrombosis & Hemostasis

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a recent observational study reported that thromboembolic risk was increased in PCOS women, but it was lower in those receiving oral contraceptives.101 Moreover, a small study reported that the increase in plasma TAFI levels observed in women with PCOS was essentially unaffected by oral contraceptive containing cyproterone acetate.32 Data about the effect of insulin sensitization on hemostatic/ fibrinolytic abnormalities of women with PCOS are also limited. However, some small intervention studies have reported a significant reduction in plasma PAI-1 concentrations after either very low calorie diet102 or metformin treatment,81,103–105 whereas discrepant results were reported on the effects of metformin on other hemostatic–fibrinolytic parameters, such as plasma t-PA and VWF levels.104,105 Very limited data also suggested a significant reduction in plasma D-dimer concentrations after metformin.82 Therapies used for ovulation induction are intrinsically short term and of limited interest in terms of potential effects on coagulation and fibrinolysis. Interestingly, it was reported that acupuncture, which was recently proposed as a nonpharmacological therapeutic approach for PCOS, may counteract a possible prothrombotic state, by lowering the circulating levels of t-PA and fibrinogen.106 However, there are no data on the risk of clinical cardiovascular events in PCOS women treated by acupuncture.

2 Mak W, Dokras A. Polycystic ovarian syndrome and the risk of

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Conclusion PCOS is a highly prevalent condition in the reproductive-aged female population. It is a complex endocrine disorder with significant clinical heterogeneity, making both diagnosis and treatment challenging. To date, the published data in the literature suggests that abnormalities of the coagulation/fibrinolytic system(s), including platelet hyperactivity and hypofibrinolysis, can be observed in patients with PCOS. Overall, these abnormalities range from mild to moderate. Whether these coagulation–fibrinolytic abnormalities are linked to the abnormal hormonal and/or metabolic system(s) in PCOS remains to be elucidated. However, it should be emphasized that the number of case– control and intervention studies is limited, and the sample size of most published studies is small. In addition, PCOS is a heterogeneous disorder and the selection of control subjects in the published studies has not been always appropriate. Finally, the strength of the few medium-quality studies is tempered by the limited number of coagulation tests performed. Future welldesigned studies in larger cohorts of PCOS patients are urgently needed to provide more adequate information on this issue. Conflict of Interest None.

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References 1 Sirmans SM, Pate KA. Epidemiology, diagnosis, and management

of polycystic ovary syndrome. Clin Epidemiol 2013;6:1–13


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cardiovascular disease and thrombosis. Semin Thromb Hemost 2009;35(7):613–620 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 Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181–191 Hanson AE. Hippocrates: Diseases of Women 1. Signs (Chic) 1975; 1:567–584 Temkin O. Soranus’ Gynecology. Book I. Baltimore, MA: The Johns Hopkins University Press; 1991 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 Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19(1):41–47 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 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 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 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 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 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 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 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 Gursoy A, Ertugrul DT, Pamuk B, et al. Mean platelet volume in patients with polycystic ovary disease. Platelets 2006;17(7): 505–506 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 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 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


614

Targher et al.

21 Kebapcilar L, Taner CE, Kebapcilar AG, Sari I. High mean platelet

39 Diamanti-Kandarakis E, Palioniko G, Alexandraki K, Bergiele A,

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 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 Yildiz BO, Bozdag G, Harmanci A, et al. Increased circulating soluble P-selectin in polycystic ovary syndrome. Fertil Steril 2010;93(7):2311–2315 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 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 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 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 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 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 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 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 Karakurt F, Gumus II, Bavbek N, et al. Increased thrombinactivatable fibrinolysis inhibitor antigen levels as a clue for prothrombotic state in polycystic ovary syndrome. Gynecol Endocrinol 2008;24(9):491–497 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 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 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 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 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 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

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 Orio F Jr, 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 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 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 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 González F, Rote NS, Minium J, Kirwan JP. Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism 2009;58(7):954–962 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 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 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 Tsanadis G, Vartholomatos G, Korkontzelos I, et al. Polycystic ovarian syndrome and thrombophilia. Hum Reprod 2002;17(2): 314–319 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 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 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 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 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 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 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 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

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Targher et al.

57 Haverkate F. Levels of haemostatic factors, arteriosclerosis and

80 Devin JK, Johnson JE, Eren M, et al. Transgenic overexpression of

cardiovascular disease. Vascul Pharmacol 2002;39(3):109–112 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 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 Olufadi R, Byrne CD. Effects of VLDL and remnant particles on platelets. Pathophysiol Haemost Thromb 2006;35(3-4):281–291 Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res 2006;98(11):1352–1364 Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP. Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol Metab 2007;18(7):280–285 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 Kim JJ, Choi YM. Dyslipidemia in women with polycystic ovary syndrome. Obstet Gynecol Sci 2013;56(3):137–142 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 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 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 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 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 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 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 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 Carmina E. Obesity, adipokines and metabolic syndrome in polycystic ovary syndrome. Front Horm Res 2013;40:40–50 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 Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007;132(6):2169–2180 Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: mechanisms and epidemiology. Thromb Haemost 2013;110(4):669–680 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 Allan CA. Sex steroids and glucose metabolism. Asian J Androl 2014;16(2):232–238 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

plasminogen activator inhibitor-1 promotes the development of polycystic ovarian changes in female mice. J Mol Endocrinol 2007; 39(1):9–16 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 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 Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 2003;24(2):183–217 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 Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008;23(3):462–477 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 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 Moghetti P. For what reasons should metformin be used in the management of polycystic ovary syndrome? J Endocrinol Invest 2012;35(1):87–89 Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014; 10(3):143–156 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 (AEPCOS) Society. J Clin Endocrinol Metab 2010;95(5):2038–2049 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 Kaunitz AM. Clinical practice. Hormonal contraception in women of older reproductive age. N Engl J Med 2008;358(12):1262–1270 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 Petitti DB. Hormonal contraceptives and arterial thrombosis—not risk-free but safe enough. N Engl J Med 2012;366(24):2316–2318 Petitti DB. Clinical practice. Combination estrogen-progestin oral contraceptives. N Engl J Med 2003;349(15):1443–1450 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 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 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 Parkin L, Sharples K, Hernandez RK, Jick SS. Risk of venous thromboembolism in users of oral contraceptives containing

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activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997;46(4):454–457 104 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):259–264 105 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):59–70 106 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


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drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 2011;342:d2139 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 casecontrol study. Hum Reprod 2003;18(3):522–526 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 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 Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen

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Hemostatic abnormalities in Noonan syndrome.

Polycystic ovary syndrome.

Polycystic ovary syndrome.

Polycystic ovary syndrome.

Metabolomics in polycystic ovary syndrome.

Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome.

Glucagon in women with polycystic ovary syndrome (PCO): relationship to abnormalities of insulin and androgens.

CLINICAL PRACTICE. Polycystic Ovary Syndrome.

Polycystic ovary syndrome: chemical pharmacotherapy.

Genetics of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS): metformin.

Polycystic ovary syndrome--phenotypes and diagnosis.

Intrauterine environment and polycystic ovary syndrome.

Adrenal disorders and polycystic ovary syndrome.

Industrial endocrine disruptors and polycystic ovary syndrome.

Endometrial adenocarcinoma and the polycystic ovary syndrome.

Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: a meta-analysis.

Gastrointestinal hormones and polycystic ovary syndrome.

Cortisol-Metabolizing Enzymes in Polycystic Ovary Syndrome.

Pregnancy complications in polycystic ovary syndrome patients.

Polycystic ovary syndrome: what's in a name?

Complementary therapy in polycystic ovary syndrome.

Dyslipidemia in women with polycystic ovary syndrome.

Neuroendocrine control in polycystic ovary-like syndrome.