Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial.

A plausible mechanism to explain thrombotic risk differences associated with the use of second- and third-generation oral contraceptives (OCs), particularly in carriers of factor V(Leiden), is still lacking. In a double-blind trial, 51 women without and 35 women with factor V(Leiden) were randomized to either a second- (30 microg ethinylestradiol/150 microg levonorgestrel) or third- (30 microg ethinylestradiol/150 microg desogestrel) generation OC. After 2 cycles of use and a wash-out of 2 cycles, the participants continued with the corresponding progestagen-only preparation. Hemostatic variables that probe the activity of the anticoagulant protein C system were determined. Compared with levonorgestrel, desogestrel-containing OCs significantly decreased protein S and increased activated protein C (APC) resistance in both groups. OCs with desogestrel had the most pronounced effects in carriers of factor V(Leiden). Progestagen-only preparations caused changes of anticoagulant parameters opposite to those of combined OCs, which in a number of cases were more pronounced with levonorgestrel. Our data show that progestagens in combined OCs counteract the thrombotic effect of the estrogen component. The higher thrombotic risk associated with third-generation OCs compared with second-generation OCs may be explained by the fact that desogestrel appeared less antithrombotic than levonorgestrel, especially in women with factor V(Leiden).

[1]  F. Rosendaal,et al.  Activated protein C resistance determined with a thrombin generation‐based test predicts for venous thrombosis in men and women , 2003, British journal of haematology.

[2]  H. Büller,et al.  Changes of hemostatic variables during oral contraceptive use. , 2003, Seminars in vascular medicine.

[3]  M. Prins,et al.  A Randomized Cross-over Study on the Effects of Levonorgestrel- and Desogestrel-containing Oral Contraceptives on the Anticoagulant Pathways , 2000, Thrombosis and Haemostasis.

[4]  M. Prins,et al.  Effects on Coagulation of Levonorgestrel- and Desogestrel-containing Low Dose Oral Contraceptives: a Cross-over Study , 2000, Thrombosis and Haemostasis.

[5]  M. Prins,et al.  Increased Fibrinolytic Activity during Use of Oral Contraceptives Is Counteracted by an Enhanced Factor XI-independent down Regulation of Fibrinolysis , 2000, Thrombosis and Haemostasis.

[6]  A. Cooney,et al.  The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites. , 2000, The Journal of endocrinology.

[7]  M. Prins,et al.  Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study , 1999, The Lancet.

[8]  C. Kluft,et al.  Importance of levonorgestrel dose in oral contraceptives for effects on coagulation , 1999, The Lancet.

[9]  R. Bertina Molecular Risk Factors for Thrombosis , 1999, Thrombosis and Haemostasis.

[10]  J. Vandenbroucke,et al.  Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. , 1999, Archives of internal medicine.

[11]  R. Bertina,et al.  A Plasma Coagulation Assay for an Activated Protein C-independent Anticoagulant Activity of Protein S , 1998, Thrombosis and Haemostasis.

[12]  U. Larsson‐cohn,et al.  Effects on the hemostatic system and liver function in relation to Implanon and Norplant. A prospective randomized clinical trial. , 1998, Contraception.

[13]  H. Bennink,et al.  A randomized controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75 μg desogestrel or 30 μg levonorgestrel , 1998 .

[14]  H. C. Coelingh Bennink,et al.  A randomized controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75 microgram desogestrel or 30 microgram levonorgestrel. , 1998, Contraception.

[15]  H. Hemker,et al.  Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second‐ and third‐generation oral contraceptives , 1997, British journal of haematology.

[16]  W. Speiser,et al.  Increased Levels of Activated Factor VII and Decreased Plasma Protein S Activity and Circulating Thrombomodulin during Use of Oral Contraceptives , 1996, Thrombosis and Haemostasis.

[17]  Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components , 1996 .

[18]  M. Elisen,et al.  Role of the A+ Helix in Heparin Binding to Protein C Inhibitor , 1996, Thrombosis and Haemostasis.

[19]  B. Dahlbäck,et al.  Molecular mechanisms of activated protein C resistance. Properties of factor V isolated from an individual with homozygosity for the Arg506 to Gln mutation in the factor V gene. , 1996, The Biochemical journal.

[20]  W. Spitzer,et al.  Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study , 1996, BMJ.

[21]  T. Farley,et al.  Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease , 1995 .

[22]  World Health Organization Collaborative Study of Cardiov Contraception Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease , 1995, The Lancet.

[23]  H. Jick,et al.  Risk of idiopathic cardiovascular death and rionfatal venous thromboembolism in women using oral contraceptives with differing progestagen components , 1995, The Lancet.

[24]  J. Vandenbroucke,et al.  Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen , 1995, The Lancet.

[25]  H. Hemker,et al.  Peptide Bond Cleavages and Loss of Functional Activity during Inactivation of Factor Va and Factor VaR506Q by Activated Protein C (*) , 1995, The Journal of Biological Chemistry.

[26]  S. Marsoni,et al.  Fluorouracil and folinic acid in colon cancer , 1995, The Lancet.

[27]  K. Mann,et al.  Characterization of the Molecular Defect in Factor VR506A(*) , 1995, The Journal of Biological Chemistry.

[28]  P. Reitsma,et al.  Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation , 1994, The Lancet.

[29]  J. Voorberg,et al.  Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V , 1994, The Lancet.

[30]  E. Adashi,et al.  Pharmacokinetics of desogestrel. , 1993, American journal of obstetrics and gynecology.

[31]  B. Alving,et al.  Recent advances in understanding clotting and evaluating patients with recurrent thrombosis. , 1992, American journal of obstetrics and gynecology.

[32]  H. Kuhl,et al.  Pharmacokinetics of oestrogens and progestogens. , 1990, Maturitas.

[33]  J. Jespersen,et al.  Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. , 1990, American journal of obstetrics and gynecology.

[34]  P. Croft,et al.  Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' oral contraception study. , 1989, BMJ.

[35]  P. Stolley,et al.  Oral contraceptives and vascular disease. , 1989, Epidemiologic reviews.

[36]  C. la Vecchia,et al.  Risk factors for myocardial infarction in young women. , 1987, American journal of epidemiology.

[37]  L. Boerger,et al.  Oral contraceptives and gender affect protein S status. , 1987, Blood.

[38]  C. Esmon,et al.  Recurrent venous thromboembolism in patients with a partial deficiency of protein S. , 1984, The New England journal of medicine.

[39]  T. Pyörälä,et al.  Effects of oral contraceptive combinations containing levonorgestrel or desogestrel on serum proteins and androgen binding. , 1981, Scandinavian journal of clinical and laboratory investigation.

[40]  B. Stadel Oral contraceptives and cardiovascular disease (first of two parts). , 1981, The New England journal of medicine.

[41]  W. Inman,et al.  Thromboembolic Disease and the Steroidal Content of Oral Contraceptives. A Report to the Committee on Safety of Drugs , 1970, British medical journal.

[42]  G. Swyer Thromboembolic disease and the steroidal content of oral contraceptives. , 1970, Research in reproduction.