Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens

Huib A.A.M. van Vliet1, Marijke Frolich2, M. Christella4, L.G.D. Thomassen4, Carine J.M. Doggen3, Frits R. Rosendaal3, Jan Rosing4 and Frans M. Helmerhorst1,5

1 Department of Gynaecology and Reproductive Medicine, 2 Department of Clinical Chemistry, 3 Department of Hematology and Clinical Epidemiology, Leiden University Medical Center, P.O.Box 9600, 2300 RC Leiden and 4 Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, P.O.Box 616, 6200 MD Maastricht, The Netherlands

5 To whom correspondence should be addressed. Email: f.m.helmerhorst{at}lumc.nl


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Epidemiological studies have shown that both the estrogen dose and progestogen type of oral contraceptives contribute to the increased risk of thrombosis in oral contraceptive users. Thrombin generation-based activated protein C (APC) sensitivity is a global test for the net prothrombotic effect of oral contraceptives and predicts the thrombotic risk. Our objective was to test the usefulness of sex hormone-binding globulin (SHBG) as a marker for the thrombotic risk of an oral contraceptive. METHODS: We measured SHBG and APC resistance in 156 healthy users of various types of oral contraceptives. RESULTS: Users of oral contraceptives with a moderately increased risk of thrombosis (gestodene and desogestrel pills) had higher SHBG levels than users of low-risk oral contraceptives containing levonorgestrel. Similarly, for higher doses of estrogen in oral contraceptives we found higher SHBG levels. Women using oral contraceptives with the highest thrombotic risk (cyproterone acetate pills) rendered the highest SHBG levels. Users of oral contraceptives containing gestodene, desogestrel or cyproterone acetate were more resistant to APC than users of levonorgestrel pills. SHBG levels were positively associated with the increased APC resistance. CONCLUSIONS: Our findings support the hypothesis that the effect of an oral contraceptive on SHBG levels might be a marker for the thrombotic risk.

Key words: APC resistance/oral contraceptives/SHBG/venous thrombosis


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Epidemiological studies have shown that both the estrogen dose as well as the progestogen type of oral contraceptives contribute to the increased risk of venous thrombosis in oral contraceptive users (Vandenbroucke et al., 2001Go). So called ‘high-dose’ oral contraceptives containing ≥50 µg ethinylestradiol are associated with a higher risk of thrombosis than ‘low-dose’ oral contraceptives containing 20–30 µg ethinylestradiol (Rosendaal et al., 2003Go). Further, combined oral contraceptives containing the third-generation progestogens gestodene and desogestrel or the progestogen cyproterone acetate are more thrombogenic than oral contraceptives containing the second-generation progestogen levonorgestrel (Kemmeren et al., 2001Go; Vasilakis-Scaramozza and Jick, 2001Go).

Use of oral contraceptives causes changes in procoagulant, anticoagulant and fibrinolytic parameters, resulting in a net prothrombotic effect (Vandenbroucke et al., 2001Go). This prothrombotic effect can be measured globally by a thrombin generation-based APC resistance test (Rosing et al., 1999Go). The test outcome predicts the risk of venous thrombosis, in users of oral contraceptives as well as in non-users and men (Tans et al., 2003Go). Supporting the epidemiological observations, users of oral contraceptives containing desogestrel, gestodene or cyproterone acetate were found more resistant to the anticoagulant action of activated protein C (APC) by this test than users of oral contraceptives containing levonorgestrel (Rosing et al., 1999Go; van Vliet et al., 2004Go). We found the same for users of a new oral contraceptive containing drospirenone, for which no post-marketing data are currently available, but which safety with regard to thrombosis has been questioned (Sheldon, 2002Go; van Vliet et al., 2004Go).

Recently a literature study and a randomized controlled trial postulated that the effect of an oral contraceptive on sex hormone-binding globulin (SHBG) levels could be an indicator for the thrombotic risk of that oral contraceptive (Odlind et al., 2002Go; van Rooijen et al., 2004Go). SHBG produced in the liver is a carrier protein for estrogen and testosterone. Estrogens cause a dose-related increase in SHBG, whereas progestogens induce a decrease of SHBG, the extent of which depends on both dose and type of progestogen (Anderson, 1974Go; El Makhzangy et al., 1979Go; van der Vange et al., 1990Go; Knopp et al., 2001Go). The type-related differences in progestogen-induced decrease of SHBG might be interpreted as differences in anti-estrogenic properties of progestogens. Thus, the effect of an oral contraceptive on SHBG levels can be seen as the sum of the estrogenic effect of ethinylestradiol and the anti-estrogenic effect of the progestogen resulting in the total estrogenicity of the pill (van Kammen et al., 1975Go; Odlind et al., 2002Go).

The literature study demonstrated a relationship between the known thrombotic risk of second-generation, third-generation and cyproterone acetate-containing oral contraceptives and the effect of the various types of oral contraceptives on SHBG (Odlind et al., 2002Go). In agreement with the increased risk of thrombosis, gestodene- and desogestrel-containing contraceptive pills were more estrogenic, i.e. increased SHBG more, than levonorgestrel-containing pills (Odlind et al., 2002Go). Oral contraceptives containing cyproterone acetate were associated with the highest SHBG levels (Odlind et al., 2002Go). A randomized controlled trial comparing SHBG levels in women using desogestrel-containing oral contraceptives and women using levonorgestrel-containing oral contraceptives confirmed the higher levels of SHBG in desogestrel-containing pill users (van Rooijen et al., 2004Go). In addition, an association between SHBG levels and the resistance to APC measured with the classical activated partial thromboplastin time-based APC resistance test was reported (van Rooijen et al., 2004Go).

To test the usefulness of SHBG as a marker for the thrombotic risk of an oral contraceptive, we compared the plasma levels of SHBG and the resistance to APC determined with a thrombin generation-based APC resistance test in users of oral contraceptives containing either second- or third-generation progestogens or drospirenone or cyproterone acetate. Our a priori hypotheses were: (i) the plasma levels of SHBG in women using oral contraceptives known to confer an increased risk of venous thrombosis are higher than in women using contraceptive pills with levonorgestrel; and (ii) the resistance to APC in women using oral contraceptives follows the same pattern and is associated with SHBG levels.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Study design and participants
Healthy women using the same type of oral contraceptive for at least four cycles were recruited by advertising in local newspapers, public and university buildings, student houses, pharmacies and general practitioners' waiting rooms. Exclusion criteria were age (<18 years) and contraindications for oral contraceptive use as stated by World Health Organization (1996)Go. After inclusion, women completed a standardized questionnaire covering questions on risk factors for venous thrombosis. Blood samples were drawn between days 18 and 21 of the menstrual cycle. After the blood donation, drospirenone- or cyproterone acetate-containing oral contraceptive users were requested to switch to a second-generation oral contraceptive composed of 150 µg levonorgestrel and 30 µg ethinylestradiol (Microgynon-30®; Schering) and second- or third-generation oral contraceptive users were asked to switch to the drospirenone-containing oral contraceptive. A second blood sample was taken between days 18 and 21 of the fourth cycle after the change of type of oral contraceptive.

The Medical Ethics Committee of the Leiden University Medical Center, Leiden, The Netherlands approved the study. All volunteers gave written informed consent.

Risk ranking per oral contraceptive
Based on the risk of thrombosis reported in the literature, we can rank oral contraceptives by estrogen dose and progestogen type. High-dose oral contraceptives containing ≥50 µg ethinylestradiol have been associated with a higher risk of thrombosis than low-dose oral contraceptives containing 20–30 µg ethinylestradiol (Gerstman et al., 1991Go). Data from the ongoing Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study indicate a 1.9-fold higher risk of thrombosis with a 10 µg increase in estrogen dose (van Hylckama Vlieg, 2003Go). Concerning the progestogen component, it was shown that combined oral contraceptives containing the third-generation progestogens gestodene and desogestrel or the progestogen cyproterone acetate are more thrombogenic than oral contraceptives containing the second-generation progestogen levonorgestrel. A recent meta-analysis concluded that gestodene- and desogestrel-containing oral contraceptives increases the risk of thrombosis by a factor 1.5–1.7 compared to levonorgestrel-containing oral contraceptives (Kemmeren et al., 2001Go). Oral contraceptives containing cyproterone acetate confer the highest thrombotic risk, 3.9-fold higher than oral contraceptives containing levonorgestrel (Vasilakis-Scaramozza and Jick, 2001Go).

Laboratory methods
Blood samples were taken from the antecubital vein in the morning after an overnight abstinence from intake of food, caffeine and alcohol. Nine parts of blood were collected in one part 0.106 mol/l sodium citrate (pH 5.8). Cell-free, citrated plasma was prepared by centrifuging plasma at 2100g for 10 min at 18°C, coded and centrally stored at –80°C.

Normalized APC sensitivity ratios (nAPCsr) were determined by quantifying the effect of APC on thrombin generation (thrombin generation-based or ETP-based APC resistance test) as described before (Rosing et al., 1997Go). SHBG was measured with an immunometric assay (Immulite; DPC, USA). The sensitivity is 0.2 nmol/l; the variation coefficient according to the manufacturer ranges from 5.8 to 13% for the inter-assay variation from high to very low levels.

The samples were analysed in one series in random order. SHBG levels and APC resistance were measured without knowledge of the oral contraceptive used or any other of the participant's characteristics. The APC resistance test was performed in duplicate.

Statistical analysis
Mean SHBG plasma levels and mean nAPCsr in users of oral contraceptives containing norethindrone, levonorgestrel, norgestimate, gestodene, desogestrel, drospirenone or cyproterone acetate were calculated. A scatter diagram and a regression line were constructed with SHBG levels as the independent variable and nAPCsr as the dependent variable. The degree of association between SHBG levels and nAPCsr was measured by Pearson's correlation coefficient.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Between July and November 2002, 158 healthy women aged 18–51 years were recruited. We excluded two women, one because of a history of diabetes mellitus and one because of a history of venous thrombosis. Sixty women used a second-generation oral contraceptive containing levonorgestrel, 49 women a third-generation oral contraceptive containing gestodene, desogestrel or norgestimate, 23 women a drospirenone-containing contraceptive pill, 22 women an oral contraceptive containing cyproterone acetate and two women a first-generation oral contraceptive containing norethindrone (Table I).


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Table I. Participants' characteristics

 
Forty-six women agreed to switch from oral contraceptive type, of whom 40 returned for a second blood donation. Five women in the group of switchers discontinued due to breast tenderness, increase in acne and hirsutism, pregnancy wish, a previously unreported history of high blood pressure or surgery. One woman was lost to follow-up. One participant using a cyproterone acetate-containing pill was erroneously prescribed the drospirenone pill instead of a levonorgestrel-containing oral contraceptive and as a consequence excluded from the analyses. During the study, none of the participants experienced serious adverse events.

For the analyses of the first blood donation 156 women were included, of whom 39 were included in the analysis of the second blood donation. The various groups of oral contraceptive users did not differ with respect to age and body mass index (Table I).

Users of oral contraceptives with a moderately increased risk, i.e. gestodene- and desogestrel-containing pills, had SHBG plasma levels that were higher than for users of low-risk oral contraceptives containing levonorgestrel (Table II). Likewise, for higher doses of estrogen in oral contraceptives we found higher SHBG levels, i.e. women using oral contraceptives containing 30 µg ethinylestradiol rendered higher SHBG levels than women using oral contraceptives containing 20 µg ethinylestradiol. The difference in SHBG levels between third-generation pills containing gestodene and desogestrel and second-generation pills containing levonorgestrel was observed for both 20 µg and 30 µg ethinylestradiol oral contraceptives. In the group of women taking pills containing 20 µg ethinylestradiol, mean SHBG plasma levels were 111 nmol/l (95% CI 90–131) for users of gestodene pills and 143 nmol/l (95% CI 110–175) for users of desogestrel pills, while for users of levonorgestrel pills mean SHBG levels were 63 nmol/l (95% CI 36–91). Similarly, in the group of women taking oral contraceptives containing 30 µg ethinylestradiol, mean SHBG levels were 136 nmol/l (95% CI 66–205) for users of gestodene pills and 164 nmol/l (95% CI 144–185) for users of desogestrel pills compared to 63 nmol/l (95% CI 59–67) for users of levonorgestrel pills. For oral contraceptives with the highest risk of thrombosis, i.e. cyproterone acetate-containing pills, we found the highest SHBG levels (mean 210 nmol/l; 95% CI 182–238).


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Table II. Mean thrombin generation-based normalized activated protein C sensitivity ratios (nAPCsr) and mean sex hormone-binding globulin (SHBG) levels in women using different types of oral contraceptives

 
Women using oral contraceptives with a moderate or highly increased thrombotic risk (desogestrel, gestodene and cyproterone acetate pills) had higher nAPCsr than women using oral contraceptives containing levonorgestrel (Table II). Mean nAPCsr in the group of women using 20 µg ethinylestradiol oral contraceptives were 3.4 (95% CI 2.5–4.3) for gestodene pills, 3.8 (95% CI 3.4–4.2) for desogestrel pills compared to 3.2 (95% CI 1.3–5.2) for levonorgestrel pills. In the groups of 30 µg or 35 µg ethinylestradiol oral contraceptive users mean nAPCsr were 4.2 (95% CI 3.2–5.2) for gestodene-containing oral contraceptive users, 4.2 (95% CI 3.7–4.8) for desogestrel-containing oral contraceptive users and 4.0 (95% CI 3.7–4.3) for cyproterone acetate-containing oral contraceptive users, while for users of levonorgestrel-containing oral contraceptives the mean nAPCsr was 3.0 (95% CI 2.7–3.3). Users of the recently introduced pill containing drospirenone had a mean nAPCsr similar to that of users of third-generation oral contraceptives (mean 4.1; 95% CI 3.5–4.7). After exclusion of 14 participants with the factor V Leiden mutation and five participants with the prothrombin 20210A mutation, mean nAPCsr for gestodene, desogestrel, cyproterone acetate and drospirenone oral contraceptive users all remained markedly higher than for levonorgestrel oral contraceptive users (Table III).


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Table III. Mean thrombin generation-based normalized activated protein C sensitivity ratios (nAPCsr) and mean sex hormone-binding globulin (SHBG) levels in women without the factor V Leiden or prothrombin 20210A mutation using different types of oral contraceptives

 
In the 39 women who switched from oral contraceptive type, SHBG levels and nAPCsr altered correspondingly, e.g. SHBG levels and nAPCsr decreased when switching from a cyproterone acetate-containing pill to a levonorgestrel-containing pill, and similarly, SHBG and nAPCsr increased when switching from an oral contraceptive containing levonorgestrel to an oral contraceptive containing drospirenone (Table IV).


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Table IV. Change in thrombin generation-based normalized activated protein C sensitivity ratios (nAPCsr) and sex hormone-binding globulin (SHBG) levelsin women switching from oral contraceptive type

 
SHBG plasma levels were positively associated with nAPCsr in the 156 oral contraceptive users, i.e. an increase of SHBG levels of 100 nmol/l was associated with an increase of nAPCsr of 0.7 (95% CI 0.4–0.9) over the range of measurements made. Pearson's correlation coefficient was 0.4 (P<0.001). After exclusion of 14 women with the factor V Leiden and five women with the prothrombin 20210A mutation, the beta of the regression equation slightly decreased, i.e. an elevation of SHBG levels of 100 nmol/l was associated with an elevation of the nAPCsr of 0.6 (95% CI 0.4–0.8) over the range of measurements made (Figure 1). Pearson's correlation coefficient increased to 0.5 (P<0.001).



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Figure 1. Scatter diagram and linear regression line of sex hormone-binding globulin (SHBG) plasma levels and nAPCsr in 137 women without the factor V Leiden and prothrombin 20210A mutation using different types of oral contraceptives. An increase of SHBG plasma levels of 100 nmol/l was associated with an increase of nAPCsr of 0.6 (95% CI 0.4–0.8). Pearson's correlation coefficient =0.5 (P<0.001).

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
In this study of SHBG plasma levels and prothrombotic effects among 156 healthy users of various types of oral contraceptives, we observed a positive association between the effect of an oral contraceptive on SHBG levels or estrogenicity of the formulation and the thrombotic risk of a formulation as reported in the literature. Users of oral contraceptives with a moderately increased risk, i.e. third-generation oral contraceptives containing gestodene or desogestrel, had SHBG levels that were higher than in users of low-risk, second-generation oral contraceptives containing levonorgestrel (Vandenbroucke et al., 2001Go). Similarly, for higher doses of estrogen in oral contraceptives, we observed higher SHBG plasma levels (Rosendaal et al., 2003Go). Users of oral contraceptives with the highest risk of thrombosis, i.e. cyproterone acetate-containing pills, also rendered the highest SHBG levels (Vasilakis-Scaramozza and Jick, 2001Go).

In addition, SHBG plasma levels were positively associated with the resistance to the anticoagulant action of APC determined with a thrombin generation-based APC resistance test, i.e. high SHBG levels were related to a high resistance to APC. The thrombin generation-based APC resistance test that we used in this study predicts the risk of thrombosis in users of oral contraceptives as well as in non-users and men, so the relationship between SHBG plasma levels and APC resistance supports the hypothesis that SHBG is a marker for the thrombotic risk of an oral contraceptive (Tans et al., 2003Go).

The differences in SHBG levels and resistance to APC were not the result of differences between women rather than between type of oral contraceptive, as indicated by the results in women who switched from oral contraceptive type. Switching from a highly thrombogenic pill containing cyproterone acetate to a less thrombogenic pill containing levonorgestrel resulted in a decrease of SHBG levels as well as APC resistance.

Recently, Kemmeren et al., (2004)Go postulated that the different effects of third- and second-generation oral contraceptives on the anticoagulant pathway might be explained by the observation that the effect of ethinylestradiol on anticoagulant parameters is less well counteracted by desogestrel than by levonorgestrel. In their study, progestogen-only pills did not induce changes of anticoagulant parameters or induce changes opposite to those of combined oral contraceptives containing the same dose of progestogen (Kemmeren et al., 2004Go). The divergent effects of estrogen and progestogens have also been observed with regard to SHBG, i.e. progestogen-only pills decrease SHBG in contrast with combined oral contraceptives or estrogen alone which increase SHBG levels (van Kammen et al., 1975Go; El Makhzangy et al., 1979Go; Crona et al., 1984Go). In agreement with the effect on anticoagulant parameters, the lowering effect on SHBG is more pronounced in pills containing only levonorgestrel compared to pills containing only desogestrel (Crona et al., 1984Go; Barkfeldt et al., 2001Go; Kemmeren et al., 2004Go).

In conclusion, our findings support the hypothesis that the increase of SHBG induced by a combined oral contraceptive could be interpreted as a measure of estrogenicity of a combined oral contraceptive and that estrogenicity is a factor influencing the thrombotic risk of an oral contraceptive.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We are indebted to Tamara A.Winkel and Iris Noort for performing the blood sampling, Thea C.Visser-Oppelaar and Elke J.P.Magdeleyns for performing the laboratory tests, and to Ank J.Schreijer and Ingeborg de Jonge for data management. We gratefully acknowledge all women who participated in this study.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Anderson DC (1974) Sex-hormone-binding globulin. Clin Endocrinol (Oxf) 3, 69–96.[ISI][Medline]

Barkfeldt J, Virkkunen A and Dieben T (2001) The effects of two progestogen-only pills containing either desogestrel (75 microg/day) or levonorgestrel (30 microg/day) on lipid metabolism. Contraception 64, 295–299.[CrossRef][ISI][Medline]

Crona N, Silfverstolpe G and Samsioe G (1984) Changes in serum apo-lipoprotein AI and sex-hormone-binding globulin levels after treatment with two different progestins administered alone and in combination with ethinyl estradiol. Contraception 29, 261–270.[CrossRef][ISI][Medline]

El Makhzangy MN, Wynn V and Lawrence DM (1979) Sex hormone binding globulin capacity as an index of oestrogenicity or androgenicity in women on oral contraceptive steroids. Clin Endocrinol (Oxf) 10, 39–45.[ISI][Medline]

Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV and Lundin FE (1991) Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 133, 32–37.[Abstract]

Kemmeren JM, Algra A and Grobbee DE (2001) Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. Br Med J 323, 131–134.[Abstract/Free Full Text]

Kemmeren JM, Algra A, Meijers JC, Tans G, Bouma BN, Curvers J, Rosing J and Grobbee DE (2004) Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor V Leiden mutation: a randomized trial. Blood 103, 927–933.[Abstract/Free Full Text]

Knopp RH, Broyles FE, Cheung M, Moore K, Marcovina S and Chandler WL (2001) Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel. Contraception 63, 1–11.[CrossRef][ISI][Medline]

Odlind V, Milsom I, Persson I and Victor A (2002) Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? Acta Obstet Gynecol Scand 81, 482–490.[CrossRef][ISI][Medline]

Rosendaal FR, Van Hylckama Vlieg A, Tanis BC and Helmerhorst FM (2003) Estrogens, progestogens and thrombosis. J Thromb Haemost 1, 1371–1380.[CrossRef][ISI][Medline]

Rosing J, Tans G, Nicolaes GA, Thomassen MC, Van Oerle R, van der Ploeg PM, Heijnen P, Hamulyak K and Hemker HC (1997) Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 97, 233–238.[ISI][Medline]

Rosing J, Middeldorp S, Curvers J, Thomassen MC, Nicolaes GA, Meijers JC, Bouma BN, Büller HR, Prins MH and Tans G (1999) Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 354, 2036–2040.[CrossRef][ISI][Medline]

Sheldon T (2002) Dutch GPs warned against new contraceptive pill. Br Med J 324, 869.[Free Full Text]

Tans G, van Hylckama Vlieg A, Thomassen MC, Curvers J, Bertina RM, Rosing J and Rosendaal FR (2003) Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 122, 465–470.[CrossRef][ISI][Medline]

van Hylckama Vlieg A (2003) Causes of venous thrombosis: procoagulant factors and oral contraceptives [dissertation]. Leiden University, Leiden.

van Kammen E, Thijssen JH, Rademaker B and Schwarz F (1975) The influence of hormonal contraceptives on sex hormone binding globulin (SHBG) capacity. Contraception 11, 53–59.[CrossRef][ISI][Medline]

van Rooijen M, Silveira A, Hamsten A and Bremme K (2004) Sex hormone–binding globulin—a surrogate marker for the prothrombotic effects of combined oral contraceptives. Am J Obstet Gynecol 190, 332–337.[CrossRef][ISI][Medline]

Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN and Rosendaal FR (2001) Oral contraceptives and the risk of venous thrombosis. N Engl J Med 344, 1527–1535.[Free Full Text]

van der Vange N, Blankenstein MA, Kloosterboer HJ, Haspels AA and Thijssen JH (1990) Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 41, 345–352.[ISI][Medline]

van Vliet HA, Winkel TA, Noort I, Rosing J and Rosendaal FR (2004) Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate. J Thromb Haemost, in press.

Vasilakis-Scaramozza C and Jick H (2001) Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 358, 1427–1429.[CrossRef][ISI][Medline]

World Health Organization (1996) Improving Access to Quality Care in Family Planning. Medical Eligibility Criteria for Contraceptive Use. World Health Organization, Geneva.

Submitted on August 12, 2004; accepted on October 21, 2004.





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