Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Hematology and Comprehensive Cancer Center, Unit of Coagulation Disorders, Helsinki University Hospital, Helsinki, Finland.
Acta Obstet Gynecol Scand. 2022 Oct;101(10):1102-1111. doi: 10.1111/aogs.14428. Epub 2022 Jul 31.
Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin.
We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover).
NCT02352090.
Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers.
Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.
含乙炔雌二醇（EE）的避孕药会改变凝血系统，与静脉血栓栓塞风险相关。然而，比较含 EE 和低效能雌激素（即雌二醇[E]和戊酸雌二醇[EV]）的复方口服避孕药对凝血生物标志物影响的研究有限。本研究代表了一项比较戊酸雌二醇+地诺孕素（DNG）、EE+DNG 和 DNG 单药治疗对选定凝血生物标志物的随机试验的次要结局。由于包含了含有相同孕激素的制剂，我们可以比较不同雌激素成分的具体影响。
我们招募了 59 名年龄在 18 至 35 岁之间的健康、非吸烟女性，其中 3 人中途退出。参与者被随机分配接受 9 周连续治疗，方案为 EV 2mg+DNG 2-3mg（n=20）、EE 0.03mg+DNG 2mg（n=20）或 DNG 2mg（n=19）。在基线和 9 周后采集血样。我们使用校准自动血栓图评估体外凝血情况。通过凝血酶原片段 1+2（F1+2）（凝血酶生成）和 D-二聚体（纤维蛋白转化）评估体内凝血情况。
NCT02352090。
EV+DNG 暴露后，lag 时间和达到凝血酶峰时间保持不变，而 EE+DNG 缩短了 lag 时间（平均百分比变化-24%，95%置信区间[-32%至-15%]；p<0.01）和达到凝血酶峰时间（-26%，95%置信区间[-37%至-16%]；p<0.01）。EV+DNG 诱导的凝血酶峰和内源性凝血酶潜能低于 EE+DNG（峰；+45%，95%置信区间[22%-67%] vs +147%，95%置信区间[96%-198%]；p<0.01，和内源性凝血酶潜能；+26%，95%置信区间[15%-38%] vs +64%，95%置信区间[51%-76%]；p<0.01）。EV+DNG 组 F1+2 水平中位数保持不变（p=0.22），而 EE+DNG 组 F1+2 水平在正常范围内增加（从 152pmol/L，95%置信区间[127-206]pmol/L 增加到 194pmol/L，95%置信区间[149-250]pmol/L，p=0.04）。任何一组的 D-二聚体水平的组内变化均不显著。DNG 单药治疗对这些生物标志物没有影响。
EV+DNG 暴露后，体外和体内凝血酶生成均低于 EE+DNG。EV+DNG 治疗后凝血酶生成的降低指标表明凝血潜能增强程度较低，提示 EV 可能优于 EE，作为复方口服避孕药的成分。
