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Kluft et al. question the design of our recent study regarding sex hormone-binding globulin (SHBG) as a marker for the risk of venous thrombosis during use of hormonal contraceptives [1]. They state that when measured only in women ‘on-treatment’, SHBG showed a very weak association with normalized activated protein C sensitivity ratios (nAPCsr) determined with the thrombin generation-based APC resistance test. Hence, in their opinion SHBG is not a surrogate marker for venous thrombosis. They claim this statement is supported by a recent publication of Stegeman et al. [2].

In our study [1] of 262 participants, 232 women were users of different hormonal contraceptives, of whom we only included on-treatment data. In addition, a group of 13 non-users with a regular ovulatory menstrual cycle and 17 users of the non-hormonal copper-releasing IUD were included. Kluft et al. state that the difference in correlation is due to inclusion of pre-treatment data. With pre-treatment data, they likely indicate these 13 non-users and 17 users of the copper-releasing IUD. They are correct that no correlation between SHBG and nAPCsr was found in non-users of hormonal contraceptives [2]; therefore it would have been better to exclude the group of non-users and non-hormonal contraceptive users from the correlation analysis. We re-analyzed our data without the 30 non-hormonal contraceptive users (non-users and users of the copper-releasing IUD) and found similar results: r2 = 0.468; equation, log10(SHBG) = 1.515 +  (0.163 × nAPCsr) (Fig. 1).

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Figure 1. Plot of the correlation between SHBG and nAPCsr determined in 232 users of different kinds of hormonal contraceptives, excluding non-users and users of the copper-releasing IUD. A linear correlation line and coefficient are given. Equation: log10(SHBG) = 1.515 + (0.163 × nAPCsr); r = 0.69 (P < 0.001). SHBG, sex hormone-binding globulin; nAPCsr, normalized activated protein C sensitivity ratio; IUD, intra-uterine device.

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Kluft et al. also state that in our previous publication regarding the correlation between SHBG and nAPCsr an r2 of 0.25 was reported [3]. In our recent study, SHBG data were logarithmically transformed to create normality and allow a regression analysis. Regression analysis shows that with 1 unit increase in nAPCsr, SHBG levels increase by 47.3%. Furthermore, an r2 of 0.476 was found, meaning that 47.6% of the variability of SHBG in hormonal contraceptive users can be explained by its relationship with nAPCsr. Pearson's correlation coefficient was 0.69 with a P-value < 0.001.

In conclusion, our recent study shows a clear association between SHBG and nAPCsr in hormonal contraceptive users. The difference regarding the reported correlation between nAPCsr and SHBG levels in our recent and previous publications is possibly due to a wider spread in SHBG and nAPCsr levels of the participants in our recent publication, due to a greater heterogeneity of the contraceptives used.

Our study supports the concept of Odlind et al. [4] that SHBG reflects the overall estrogenicity of a hormonal contraceptive, and thereby the risk of venous thrombosis of a hormonal contraceptive. SHBG and several coagulation factors and anticoagulant proteins are synthesized in the liver, and hormonal contraceptives, which are metabolized in the liver, might interfere with the synthesis of both SHBG and coagulation factors. Stegeman et al. [2] investigated whether increased SHBG levels are a risk factor for venous thrombosis in a causal sense. In women who did not use hormonal contraceptives they did not find an association between SHBG levels and nAPCsr or with venous thrombosis risk, but this does not imply that SHBG may not be a marker in hormonal contraceptive users. In their publication it is stated that SHBG in all likelihood is a marker for venous thrombosis in hormonal contraceptive users, but only a marker and not a cause.

We conclude that our study indicates that SHBG is a useful marker for estimating the risk of venous thrombosis of new hormonal contraceptives, a statement that is supported by the European Medicines Agency (EMA), which recommends SHBG measurement for estimation of the thrombotic safety in the development of a new combined hormonal contraceptive [5]. However, clinical case–control studies will be necessary to determine the absolute thrombotic risk of new hormonal contraceptives.

Disclosure of Conflict of Interest

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  2. Disclosure of Conflict of Interest
  3. References

The laboratory of J. Rosing acted as a reference laboratory for the ETP-based APC-resistance test in a study conducted by A. G. Schering and J. Rosing has provided expert witness testimony relating to effects of hormonal contraceptives on blood coagulation.

References

  1. Top of page
  2. Disclosure of Conflict of Interest
  3. References
  • 1
    Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, Ballieux B, van Vliet H. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012; 10: 9926.
  • 2
    Stegeman BH, Helmerhorst F, Vos HL, Rosendaal FR, van Hylckama Vlieg A. Sex hormone-binding globulin levels are not causally related wuth venous thrombosis risk inwomen not using hormonal contraceptives. J Thromb Haemost 2012; 10: 20617.
  • 3
    van Vliet HA, Frolich M, Christella M, Thomassen LG, Doggen CJ, Rosendaal FR, Rosing J, Helmerhorst FM. 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. Hum Reprod 2005; 20: 5638.
  • 4
    Odlind V, Milsom I, Persson I, Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?Acta Obstet Gynecol Scand 2002; 81: 48290.
  • 5
    Committee for Medical Products for Human Use (CHMP). Guideline on clinical investigation of steroid contraceptives in women. 2005.