Endocrine Abstracts

Objective

To compare the effects of combined oral contraceptives (COCs) containing estradiol valerate (EV) and dienogest (DNG) with ethinyl estradiol (EE) and DNG on biomarkers of coagulation: thrombin generation (TG), prothrombin fragments F1+2 (F1+2) and D-dimer (D-Di). A DNG-only preparation was included as a control.

Background

COC use increases the risk of venous thromboembolism (VTE) 2-6-fold compared with non-use. Traditional COCs contain synthetic EE. However, COCs containing natural estrogens, estradiol (E2) or EV have recently been introduced, with the expectation of a reduced impact on coagulation and potentially a lower VTE risk.

Study design

We performed a randomized clinical trial and report here the secondary outcomes. Fifty-nine 18-35-year-old, healthy, normal-weight, non-smoking voluntary women were randomized to either EV+DNG (2 mg+2–3 mg, n = 20), EE+DNG (0.03 mg+2 mg, n = 20), or DNG-only (2 mg, n = 19) for nine weeks. Three women discontinued, two women with FV Leiden mutation were excluded and two samples could not be analyzed (EV+DNG n = 18, EE+DNG n = 18, DNG n = 16). We assessed TG (with Calibrated Automated Thombogram, TG-CAT), F1+F2 and D-Di at baseline and nine weeks of treatment. From the TG-CAT, we analyzed endogenous thrombin potential (ETP, total amount of thrombin), thrombin peak (highest concentration), lag time (time from initiation to thrombin burst), and time to thrombin peak (time from initiation to peak).

Results

Mean ETP increased +23% in the EV+DNG-group vs. +61% in the EE+DNG-group (P <0.01), and peak thrombin increased +40 vs. +127% (P <0.01). Mean lag time and time- to- peak thrombin decreased: -7% vs. -26% (P <0.01) and -8% vs. -21% (P <0.01). In the EE+DNG-group the within-group differences for all TG-CAT variables were significant (P <0.01). In contrast, in the EV+DNG-group only the change from baseline in ETP and peak thrombin were significant (P <0.01). Mean F1+2 and D-Di decreased in the EV+DNG and increased in the EE+DNG -group compared with baseline (EV+DNG F1+2 -9% vs. EE+DNG +16%, P = 0.04 and D-Di -0.4% vs. +10%, P = 0.06), In the DNG-only group, we did not observe any significant changes.

Conclusions

Our results indicate that the estrogen component accounts for most alterations in coagulation activity induced by COC use. We suggest that COCs containing E2/EV have less impact on thrombin generation and thereby likely decreased VTE risk compared with preparations containing EE. The actual VTE risk for E2-based COCs will be revealed in future epidemiological studies.