Objective-To compare the effects of intranasal and oral administration of 17-estradiol (E 2 ) and norethisterone (acetate) [NET(A)] in healthy postmenopausal women on activated protein C (APC) resistance and other hemostatic parameters associated with venous thrombosis. Methods and Results-In this 2-center, randomized, double-blind, 1-year trial, 90 postmenopausal women (56.6Ϯ4.7 years of age) received daily either an intranasal spray with 175 g/275 g E 2 /NET (nϭ47) or 1 mg/0.5 mg oral E 2 /NETA (nϭ43). Normalized APC sensitivity ratios (nAPCsr) were determined with a thrombin generation-based APC resistance test. After 1 year, the increase in nAPCsr was smaller in the intranasal than in the oral group: 11% (95% CI, 1% to 22%) versus 53% (95% CI, 37% to 72%). Overall, the decrease in antithrombin and increase in prothrombin fragment 1ϩ2 (F1ϩ2) were smaller and the decrease in free protein S larger in the intranasal compared with the oral group after 1 year. In both groups, the decreases in protein C and prothrombin, and the increase in D-dimer were similar.
Conclusion-Compared