Context: The use of combined hormonal contraceptives with ethinyl estradiol (EE) and a progestin results in alterations in potential biomarkers of venous thromboembolism risk. Evaluation of the impact of delivery route on these changes is difficult due to an interaction between EE and the progestin component.

Objective: To compare the impact of oral and vaginal administration of EE alone on hemostatic variables and estrogen-sensitive liver proteins.

Design: This was single-center, randomized, cross-over study with 2 treatment cycles separated by a washout cycle.

Setting: An academic outpatient center.

Participants: Fourteen healthy postmenopausal women were enrolled; 13 completed the study and were included in the analyses.

Intervention: Participants were randomized to receive EE (15 µg/day) delivered by oral tablet or vaginal ring for 21 days in 1 of 2 treatment sequences.

Main outcome measures: Changes in plasma concentration or activity of 10 hemostatic variables and 6 estrogen-sensitive liver proteins between baseline and day 21 of treatment.

Results: Prothrombin fragment 1 + 2 plasma level was unaffected by treatment or delivery route. Angiotensinogen (expressed as plasma level of angiotensin I) increased similarly with oral and vaginal delivery: mean (SD) increases were 2757 (1033) and 2864 (893) ng /mL, respectively (P = 0.0002). Alterations in other study variables, except total cholesterol, were similar with oral and vaginal administration.

Conclusion: Our results provide evidence that the customary effects of combined hormonal contraceptives on hemostatic variables and estrogen-sensitive liver proteins are largely related to EE and independent of delivery route during short-term treatment.