Low Thrombin Generation in Users of a Contraceptive Containing Estetrol and Drospirenone

Laure Morimont; Maud Jost; Ulysse Gaspard; Jean-Michel Foidart; Jean-Michel Dogné; Jonathan Douxfils


J Clin Endocrinol Metab. 2023;108(1):135-143. 

In This Article

Abstract and Introduction


Objective: To compare the impact on thrombin generation of the new combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone with ethinylestradiol (30 or 20 mcg) associated either with 150 mcg levonorgestrel or with 3 mg drospirenone.

Methods: Data were collected from the "E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study" (NCT02957630). Overall, the per-protocol set population included 24 subjects in the ethinylestradiol/levonorgestrel arm, 28 subjects in the ethinylestradiol/drospirenone arm, and 34 subjects in the estetrol/drospirenone arm. Thrombograms and thrombin generation parameters (lag time, peak, time to peak, endogenous thrombin potential, and mean velocity rate index) were extracted for each subject at baseline and after 6 cycles of treatment.

Results: After 6 cycles of treatment, ethinylestradiol-containing products arms show a mean thrombogram outside the upper limit of the reference range, that is the 97.5th percentile of all baseline thrombograms. On the other hand, the mean thrombogram of estetrol/drospirenone is within this reference interval. After 6 cycles of treatment, all thrombin generation parameters are statistically less affected by estetrol/drospirenone than ethinylestradiol-containing products.

Conclusions: In conclusion, an association of 15 mg estetrol with 3 mg drospirenone does not have an impact on thrombin generation compared with ethinylestradiol-containing products that, either associated with levonorgestrel or drospirenone, are able to increase the production of procoagulant factors and decrease the production of anticoagulant ones, shifting the patient to a prothrombotic state. Ethinylestradiol-containing products thus generate prothrombotic environments contrary to estetrol which demonstrates a neutral profile on hemostasis.


Pregnancy and postpartum, as well as exogenous hormones exposure, such as combined hormonal contraceptives (CHCs), create hormonal changes associated with an increased risk of venous thromboembolism (VTE).[1] Indeed, a 5-fold increased risk of VTE is reported during pregnancy, and up to a 20- to 60-fold increased risk in the postpartum period (ie, during the first 6 weeks after delivery).[2–4] For women using CHCs, the relative risk varies between 1.3 and 5.6, depending on the estroprogestative association and the dose of the estrogenic component.[5–11]

Pregnancy and the use of CHCs cause changes in plasma levels of almost all proteins involved in the coagulation and fibrinolysis.[12] These changes might be considered relatively modest when measured separately, but they could have a supra-additive effect leading to a procoagulable state responsible for this increased risk of VTE.[13] Overall, rises in coagulation factors II, V, VII, VIII, IX, X, XI, and XII and von Willebrand factor, as well as fibrinogen levels, are observed.[12] On the other hand, antithrombin, protein S, and tissue factor pathway inhibitor (TFPI) levels, 3 proteins contributing to the anticoagulant system, are decreased.[14–17] As for the fibrinolysis, there is an increase in plasminogen levels but a decrease in tissue plasminogen activator antigens and plasminogen activator inhibitor-1 levels.[12] These hormonal changes, both during pregnancy and after the use of hormonal therapy, are also associated with activated protein C (APC) resistance, which can result from increases in FII, FVIII, or FX levels and/or decreases in protein S and TFPI.[12,13,18,19]

Among assays measuring APC resistance, the endogenous thrombin potential (ETP)-based APC resistance assay is the most sensitive toward acquired APC resistance and has been linked to an increased risk of VTE in women on hormonal therapy.[13–19] This technique relies on the thrombin generation assay (TGA), which permits to obtain a thrombogram (ie, a visual and quantitative representation of the amount of thrombin generated over time in a cupule). Although the normalized activated protein C sensitivity ratio (nAPCsr) reflects the capacity of the ETP parameter (representing the area under the thrombogram) to be reduced in the presence of exogenous APC, other parameters of the thrombogram can be exploited.[20] Indeed, they can provide information on the prothrombotic tendency,[21,22] independently of the resistance toward exogenous APC. Besides, the use of ethinylestradiol (EE) based-CHCs, and other known hypercoagulable states, have been shown to enhance in vitro thrombin generation.[23–25]

A combination of 15 mg estetrol (E4) and 3 mg drospirenone (DRSP) (Nextstellis in the United States, Drovelis and Lydisilka in Europe) has recently been approved.[26] Estetrol is a natural and native fetal estrogen synthesized exclusively in the human fetal liver.[27] It has a unique mode of action, different from those of other estrogens, by activating the nuclear estrogen receptor α but antagonizing the membrane estrogen receptor α.[28] The use of E4 demonstrated a low impact on the liver with minimal effects on lipids, lipoproteins, sex hormone binding globulin (SHBG), and several coagulation and fibrinolytic proteins.[29] The association of E4 with DRSP also showed a much lower impact on APC resistance compared with EE with levonorgestrel (LNG) or EE with DRSP as well as on the level of prothrombin fragment 1+2, a marker of the ongoing coagulation.[29] Nevertheless, although some coagulation factors such as prothrombin, FVII, TFPI, or protein S were individually affected by each of these therapies (ie, E4/DRSP, EE/LNG, and EE/DRSP), the synergistic effect of these changes on hemostasis could not be captured by these singular measurements. Therefore, a global test capable of capturing all pro- and anticoagulants factors levels changes would allow a more accurate evaluation of the impact of a CHC on hemostasis and the associated risk of VTE. The thrombin generation test permits assessment of the coagulation process in its entirety and it has been shown to be sensitive to the synergistic hemostatic alterations induced by CHCs.[30] This study aims therefore at comparing the impact of E4/DRSP with EE/LNG and EE/DRSP on thrombin generation.