Elsevier

Contraception

Volume 70, Issue 2, August 2004, Pages 97-106
Contraception

Original research article
Effect of four oral contraceptives on hemostatic parameters

https://doi.org/10.1016/j.contraception.2004.03.004Get rights and content

Abstract

This is the first double-blind, controlled, randomized study comparing the effect of different estrogen components in oral contraceptives (OCs) on hemostasis variables. Four groups of 25 women each were treated for six cycles with monophasic combinations containing 21 tablets with either 30 μg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 μg EE + 2 mg DNG (20EE/DNG), 10 μg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 μg EE + 100 μg levonorgestrel (LNG) (EE/LNG). Blood samples were taken on Days 21–26 of the control cycle and on Days 18–21 of the first, third and sixth treatment cycle. Treatment with all four OCs caused an increase in levels of fibrinogen, prothrombin fragment 1+2, D-dimer, plasminogen, plasmin-antiplasmin complex and an increase in protein C activity, a decrease in antithrombin activity, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI), and a slight decrease in the sensitivity to activated protein C, but no significant change in that of the thrombin-antithrombin complex. In users of the DNG-containing OCs, the reduction in total and free protein S, and in t-PA and PAI was dependent on the EE dose, while factor VII activity was elevated, but not significantly different from EE/LNG. The results are in agreement with those of previous studies. The effects of EE/EV/DNG on total and free protein S and on t-PA and PAI were lower than those of 20EE/DNG, suggesting that the impact of 2 mg EV on several hemostasis variables is less than that of 10 μg EE. The results show an antagonistic effect of LNG on the EE-induced rise of factor VII activity and fragment 1+2 and on the EE-dependent reduction of total and free protein S.

Introduction

Several case-control and cohort studies have reported on an association between use of oral contraceptives (OCs) and the risk of venous thromboembolic events (VTEs). The decrease in the incidence of VTEs after introduction of low-dose OCs containing ≤35 μg ethinylestradiol (EE) suggested a causal connection with the dose of the estrogen component [1], [2], [3], [4], [5]. This appeared to be plausible because changes in coagulation and fibrinolysis variables were significantly lower in OCs with 30 μg EE than with 50 μg EE [6]. Therefore, development of new OC formulations was characterized by the intention to further reduce the EE dose to ≤20 μg, which had to be compensated for by more potent progestins in order to maintain the contraceptive efficacy.

Reports on a higher VTE risk during use of low-dose OCs containing the so-called third-generation progestins as compared to OCs containing levonorgestrel (LNG) or norethisterone, led to controversial discussions [5], [7], [8], [9], [10], [11]. However, subsequent findings suggested that progestins might play a role in the development of VTEs during the use of OCs, as there were differences in their effects on the intrinsic and extrinsic procoagulant activity [6], [12], [13], [14], [15], [16]. An unfavorable effect of the progestin component might prevent further reduction of risk of VTEs when using OCs with 20 μg EE. Although when taken alone progestins have no or only minor effects on hemostasis, they can modify the action of EE on certain coagulation and fibrinolysis parameters, depending on their androgenic activity [6], [12], [14]. The changes in hemostasis parameters observed during clinical studies cannot explain the association between OC use and increased risk of VTEs. In patients with risk factors, e.g., deficiencies of coagulation inhibitors or resistance to activated protein C, OCs may enhance a preexisting imbalance in the control of coagulation [17]. Such a predisposition might explain the observation that the risk is highest in the first year of OC use [5].

Natural estrogens like estradiol (E2) are believed to be associated with a lower risk of VTE than EE, because their effect on hemostasis parameters is weaker. In a small study with 21 healthy oophorectomized women, 4 developed a venous thrombosis within 80 days of treatment with 20 μg mestranol, which is rapidly converted to EE after intake [18].

Attempts to use E2 or estradiol valerate (EV) in combined OCs were not very successful, because rate of irregular bleeding was high. This has been found to be due to the progestin-induced stimulation of endometrial 17β-hydroxysteroid dehydrogenase, which causes a rapid local inactivation of E2. Contrary to this, EE cannot be metabolized by this enzyme, as the ethinyl group blocks oxidation of the 17β-hydroxy group. Therefore, it has been proposed to stabilize the cycle control of combined OCs containing E2, by the addition of 10 μg EE [19]. Indeed, treatment of fertile women with a combination of 10 μg EE + 2 mg EV and 2 mg dienogest (DNG) caused a reliable suppression of ovulation and good cycle control [20].

In the present study, the effect on various hemostasis parameters of this new formulation was compared with that of combinations of 2 mg DNG with either 20 μg or 30 μg EE and a preparation with 20 μg EE and 100 μg LNG. This trial was carried out to examine whether partial replacement of EE by a natural estrogen would result in less impact on hemostasis. Moreover, the effect of LNG, a progestin with androgenic properties, was compared with that of DNG, the only nortestosterone derivative with an antiandrogenic effect.

Section snippets

Study design

The double-blind, controlled, randomized study was carried out at two centers (Essen and Frankfurt). Included in this study were 100 healthy volunteers between 18 and 35 years of age with regular menstrual cycles and without contraindications for use of OCs. The women had not used any hormonal medication for at least 4 weeks prior to the study and did not use drugs that were known to influence the effects of OCs.

A general and gynecological examination including a Papanicolaou (Pap) smear and a

Results

Screening was carried out with 110 subjects, and 100 were randomized to receive one of four medications. Eight subjects discontinued the study prematurely, and no data from the treatment phase were available from one subject. Ninety-one subjects completed the study. Reasons for discontinuation were: bleeding abnomalities (n = 1); withdrawal of consent (n = 1); inclusion criteria not met (n = 1); did not appear for final examination (n = 1); adverse events (n = 2); pregnancy (n = 1); other (n =

Discussion

Most studies investigating the effects of OCs on hemostasis parameters showed an increase in both the procoagulant and the fibrinolytic activity, suggesting a shift of the equilibrium between coagulation and fibrinolysis to a higher level of fibrin turnover as indicated by a rise in the levels of prothrombin fragment 1+2 and D-dimer-fibrin split products. Most of the changes in hemostasis parameters were caused by the estrogen component, but only some of them, e.g., factor VII activity,

Acknowledgements

The study was financially supported by Jenapharm GmbH & Co KG, Jena, Germany). The support of Mrs. Sonja Hägele (Jenapharm GmbH & Co KG) who did the language reviewing, of Dr. Claudia Moore (Jenapharm GmbH & Co KG) who was responsible for the planning and performance of the study, and of Dr. Uwe Mellinger (Jenapharm GmbH & Co KG) who did the statistical evaluation of the results, is gratefully acknowledged.

References (68)

  • J Spona et al.

    Double-blind, randomized, placebo-controlled study on the effects of the monophasic oral contraceptive containing 30 μg ethinylestradiol and 2 mg dienogest on the hemostatic system

    Contraception

    (1997)
  • U.H Winkler et al.

    A comparative study on the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 μg and 30 μg ethinylestradiol

    Contraception

    (1996)
  • R.N.V Prasad et al.

    Effects of three types of combined OC pills on blood coagulation, fibrinolysis and platelet function

    Contraception

    (1989)
  • A Kjaer et al.

    Lipid metabolism and coagulation of two contraceptivescorrelation to serum concentrations of levonorgestrel and gestodene

    Contraception

    (1989)
  • H Refn et al.

    Metabolic changes during treatment with two different progestins

    Am J Obstet Gynecol

    (1990)
  • G Plu-Bureau et al.

    Factor VII activation and oral contraceptives

    Thromb Res

    (1993)
  • I Wiegratz et al.

    Effect of dienogest-containing oral contraceptives on lipid metabolism

    Contraception

    (2002)
  • A.C Cachrimanidou et al.

    Hemostasis profile and lipid metabolism with long-interval use of a desogestrel-containing oral contraceptive

    Contraception

    (1994)
  • D.F Archer et al.

    The effects of a low-dose monophasic preparation of levonorgestrel and ethinyl estradiol on coagulation and other hemostatic factors

    Am J Obstet Gynecol

    (1999)
  • R.T Burkman et al.

    Oral contraceptives and antithrombin IIIvariations by dosage and ABO blood group

    Am J Obstet Gynecol

    (1991)
  • J Bonnar

    Coagulation effects of oral contraception

    Am J Obstet Gynecol

    (1987)
  • K.R Petersen et al.

    Effects of monophasic low-dose oral contraceptives on fibrin formation and resolution in young women

    Am J Obstet Gynecol

    (1993)
  • E Melissari et al.

    The effects of oestrogen administration on the plasma free protein S and C4b-binding protein

    Thromb Res

    (1988)
  • C Kluft et al.

    Importance of levonorgestrel dose in oral contraceptives for effects on coagulation

    Lancet

    (1999)
  • J Rosing et al.

    Low-dose oral contraceptives and acquired resistance to activated protein Ca randomised cross-over study

    Lancet

    (1999)
  • M.C.H de Visser et al.

    A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis

    Blood

    (1999)
  • L.A.J Heinemann et al.

    The association between activated protein C resistance and venous thromboembolism in women

    Contraception

    (2002)
  • L Daly et al.

    Comparative studies of 30 μg ethinyl estradiol combined with gestodene and desogestrel on blood coagulation, fibrinolysis and platelets

    Am J Obstet Gynecol

    (1990)
  • A Dahm et al.

    Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis

    Blood

    (2003)
  • B.B Gerstman et al.

    Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease

    Am J Epidemiol

    (1991)
  • O Lidegaard

    Oral contraception and risk of a cerebral thromboembolic attackresults of a case-control study

    BMJ

    (1993)
  • R.D.T Farmer et al.

    The risk of venous thromboembolism associated with low oestrogen oral contraceptives

    J Obstet Gynaecol

    (1995)
  • F.M Helmerhorst et al.

    Venous thromboembolism and the pill. The WHO technical report on cardiovascular disease and steroid hormone contraceptionstate-of-the-art

    Hum Reprod

    (1998)
  • A Sabra et al.

    Hemostatic changes induced by 50 μg and 30 μg estrogen/progestin oral contraceptives. Modification of estrogen effects by levonorgestrel

    J Reprod Med

    (1983)
  • Cited by (0)

    View full text