Download PDF
Thromb Haemost 2017; 117(11): 2053-2062
DOI: 10.1160/TH17-04-0248
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Differential Effects on Haemostatic Markers by Metformin and the Contraceptive Pill: A Randomized Comparative Trial in PCOS

Genia F. Burchall
,
Terrence J. Piva
,
Sanjeeva Ranasinha
,
Helena J. Teede
Further Information

Publication History

10 April 2017

14 July 2017

Publication Date:
30 November 2017 (online)

    Permissions and Reprints

Abstract

Background Polycystic ovarian syndrome (PCOS) affects up to 18% of reproductive-aged women with increased risks of cardiovascular disease and venous thromboembolic disease, related to metabolic and hormonal features, obesity and an apparent hypofibrinolytic state, possibly exacerbated by current PCOS treatments.

Objective To investigate and compare haemostatic impacts of common pharmacological treatments and explore relationships with hormonal and metabolic variables in PCOS.

Patients/Methods This mechanistic sub-study using biobanked samples from a 6-month randomized comparative trial of pharmacological treatments assessed pro- and anti-thrombotic markers and overall haemostatic activity. Overweight women of mean age 33.9 ± 6.7 years and mean BMI (body mass index) of 36.5 ± 7.0 kg/m2 with PCOS (n = 60) were randomized to either metformin, higher-dose oral contraceptive pill (OCP) or low-dose OCP + spironolactone (OCP + S). Primary outcome measures included changes in plasminogen activator inhibitor 1 (PAI-1), asymmetric dimethylarginine (ADMA), prothrombin fragments 1 and 2 (PF1 and 2), plasminogen, tissue plasminogen activator (tPA), thrombin activatable fibrinolysis inhibitor (TAFI) and thrombin generation (TG).

Results PAI-1 activity fell in all groups, ADMA fell in higher-dose OCP, PF1 and 2 increased with metformin and higher-dose OCP, TG rose and tPA fell in both OCP groups, plasminogen increased in all and TAFI increased after higher-dose OCP.

Conclusion Endothelial function (primary haemostasis) improved with higher dose with some improvement in low-dose OCP + S and metformin. Aberrant coagulation was noted in both OCP groups, but not with metformin. Fibrinolysis was reduced with higher-dose OCP. Our work suggests an additional dimension of treatment (haemostatic system effects) that favours metformin treatment over the OCP in PCOS.

Keywords

fibrinolysis - haemostasis - metformin - oral contraceptives - polycystic ovary syndrome

Work Performed at

School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia.


Disclosure Statement

The authors have nothing to disclose.


Grant Support

Helen MacPherson Smith Trust


 

  • References

  • 1 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81 (01) 19-25
    CrossrefPubMedGoogle Scholar
  • 2 Teede HJ, Misso ML, Deeks AA. , et al; Guideline Development Groups. Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust 2011; 195 (06) S65-S112
    CrossrefPubMedGoogle Scholar
  • 3 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 (02) 544-551
    CrossrefPubMedGoogle Scholar
  • 4 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
  • 5 Hayes MG, Urbanek M, Ehrmann DA. , et al; Reproductive Medicine Network. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 2015; 6: 7502
    CrossrefPubMedGoogle Scholar
  • 6 Moran LJ, Norman RJ, Teede HJ. Metabolic risk in PCOS: phenotype and adiposity impact. Trends Endocrinol Metab 2015; 26 (03) 136-143
    CrossrefPubMedGoogle Scholar
  • 7 Teede HJ, Joham AE, Paul E. , et al. Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. Obesity (Silver Spring) 2013; 21 (08) 1526-1532
    CrossrefPubMedGoogle Scholar
  • 8 Hart R, Doherty DA. The potential implications of a PCOS diagnosis on a woman's long-term health using data linkage. J Clin Endocrinol Metab 2015; 100 (03) 911-919
    CrossrefPubMedGoogle Scholar
  • 9 Bird ST, Hartzema AG, Brophy JM, Etminan M, Delaney JA. Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis. CMAJ 2013; 185 (02) E115-E120
    CrossrefPubMedGoogle Scholar
  • 10 Burchall GF, Piva TJ, Linden MD, Gibson-Helm ME, Ranasinha S, Teede HJ. Comprehensive assessment of the hemostatic system in polycystic ovarian syndrome. Semin Thromb Hemost 2016; 42 (01) 55-62
    PubMedGoogle Scholar
  • 11 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 (01) 6-14
    CrossrefPubMedGoogle Scholar
  • 12 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
  • 13 Stewart M, Black K. Choosing a combined oral contraceptive pill. Aust Prescr 2015; 38 (01) 6-11
    CrossrefPubMedGoogle Scholar
  • 14 Soares GM, Vieira CS, de Paula Martins W, Dos Reis RM, de Sá MF, Ferriani RA. Metabolic and cardiovascular impact of oral contraceptives in polycystic ovary syndrome. Int J Clin Pract 2009; 63 (01) 160-169
    CrossrefPubMedGoogle Scholar
  • 15 Meyer C, McGrath BP, Teede HJ. Effects of medical therapy on insulin resistance and the cardiovascular system in polycystic ovary syndrome. Diabetes Care 2007; 30 (03) 471-478
    CrossrefPubMedGoogle Scholar
  • 16 Naderpoor N, Shorakae S, de Courten B, Misso ML, Moran LJ, Teede HJ. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update 2016; 22 (03) dmv063
    PubMedGoogle Scholar
  • 17 Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr 2013; 5 (01) 6
    CrossrefPubMedGoogle Scholar
  • 18 Belfiore F, Mogensen CE. New Concepts in Diabetes and Its Treatment. New York, NY: Karger; 2000
    Google Scholar
  • 19 Teede HJ, Meyer C, Hutchison SK, Zoungas S, McGrath BP, Moran LJ. Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Fertil Steril 2010; 93 (01) 184-191
    CrossrefPubMedGoogle Scholar
  • 20 Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag 2005; 1 (03) 183-198
    PubMedGoogle Scholar
  • 21 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
  • 22 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 (03) 207-214
    CrossrefPubMedGoogle Scholar
  • 23 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 (02) 110-116
    CrossrefPubMedGoogle Scholar
  • 24 Glueck CJ, Wang P, Goldenberg N, Sieve L. Pregnancy loss, polycystic ovary syndrome, thrombophilia, hypofibrinolysis, enoxaparin, metformin. Clin Appl Thromb Hemost 2004; 10 (04) 323-334
    CrossrefPubMedGoogle Scholar
  • 25 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 (02) 236-241
    CrossrefPubMedGoogle Scholar
  • 26 Lin S, Yongmei G. Plasminogen activator and plasma activator inhibitor-1 in young women with polycystic ovary syndrome. Int J Gynaecol Obstet 2008; 100 (03) 285-286
    CrossrefPubMedGoogle Scholar
  • 27 Sills ES, Drews CD, Perloe M, Tucker MJ, Kaplan CR, Palermo GD. Absence of profound hyperinsulinism in polycystic ovary syndrome is associated with subtle elevations in the plasminogen activator inhibitor system. Gynecol Endocrinol 2003; 17 (03) 231-237
    CrossrefPubMedGoogle Scholar
  • 28 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 (06) 793-798
    CrossrefPubMedGoogle Scholar
  • 29 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 (05) 505-510
    CrossrefPubMedGoogle Scholar
  • 30 Macut D, Micić D, Cvijović G. , et al. Cardiovascular risk in adolescent and young adult obese females with polycystic ovary syndrome (PCOS). J Pediatr Endocrinol Metab 2001; 14 (Suppl. 05) 1353-1359 , discussion 1365
    PubMedGoogle Scholar
  • 31 Rajendran S, Willoughby SR, Chan WP. , et al. Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects. Atherosclerosis 2009; 204 (02) 509-514
    CrossrefPubMedGoogle Scholar
  • 32 Ozgurtas T, Oktenli C, Dede M. , et al. Metformin and oral contraceptive treatments reduced circulating asymmetric dimethylarginine (ADMA) levels in patients with polycystic ovary syndrome (PCOS). Atherosclerosis 2008; 200 (02) 336-344
    CrossrefPubMedGoogle Scholar
  • 33 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 (01) 82-90
    CrossrefPubMedGoogle Scholar
  • 34 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 (02) 958-965
    CrossrefPubMedGoogle Scholar
  • 35 Karakurt F, Carlioglu A, Kaygusuz I, Gumus II, Uz B, Akdeniz D. Effect of ethinyl estradiol-cyproterone acetate treatment on asymmetric dimethyl-arginine levels in women with polycystic ovary syndrome. Arch Gynecol Obstet 2014; 289 (01) 135-140
    CrossrefPubMedGoogle Scholar
  • 36 Kilic S, Yilmaz N, Zulfikaroglu E, Erdogan G, Aydin M, Batioglu S. Inflammatory-metabolic parameters in obese and nonobese normoandrogenemic polycystic ovary syndrome during metformin and oral contraceptive treatment. Gynecol Endocrinol 2011; 27 (09) 622-629
    CrossrefPubMedGoogle Scholar
  • 37 Koiou E, Tziomalos K, Katsikis I, Delkos D, Tsourdi EA, Panidis D. Disparate effects of pharmacotherapy on plasma plasminogen activator inhibitor-1 levels in women with the polycystic ovary syndrome. Hormones (Athens) 2013; 12 (04) 559-566
    CrossrefPubMedGoogle Scholar
  • 38 Tan BK, Adya R, Chen J. , et al. Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc Res 2009; 83 (03) 566-574
    CrossrefPubMedGoogle Scholar
  • 39 Song J, Shen H, Li J, Huang Z, Zhang Y. Effects of metformin on the plasminogen activator system, endocrine, metabolic profiles in patients with polycystic ovary syndrome and clomiphene resistant cases [in Chinese]. Zhonghua Fu Chan Ke Za Zhi 2002; 37 (02) 86-89
    PubMedGoogle Scholar
  • 40 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 (04) 454-457
    CrossrefPubMedGoogle Scholar
  • 41 Chaireti R. Thrombin Generation in Different Cohorts: Evaluation of the Haemostatic Potential [doctoral thesis]. Linköping, Sweden: Linköping University; 2013
    Google Scholar
  • 42 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 (03) 469-480
    CrossrefPubMedGoogle Scholar
  • 43 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 (09) 491-497
    CrossrefPubMedGoogle Scholar
  • 44 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 (04) 259-264
    PubMedGoogle Scholar
  • 45 Stegeman BH, de Bastos M, Rosendaal FR. , et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ 2013; 347: f5298
    CrossrefPubMedGoogle Scholar
  • 46 Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil Steril 2017; 107 (01) 43-51
    CrossrefPubMedGoogle Scholar
  • 47 Oslakovic S, Zadro R. Comparison of the impact of four generations of progestins on hemostatic variables. Clin Appl Thromb Hemost 2014; 20 (04) 448-455
    CrossrefPubMedGoogle Scholar
  • 48 Middeldorp S, Meijers JC, van den Ende AE. , et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost 2000; 84 (01) 4-8
    Article in Thieme ConnectPubMedGoogle Scholar