Less effect of intranasal than oral hormone therapy on factors associated with venous thrombosis risk in healthy postmenopausal women.

OBJECTIVE To compare the effects of intranasal and oral administration of 17beta-estradiol (E2) 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 (56.6+/-4.7 years of age) received daily either an intranasal spray with 175 microg/275 microg E2/NET (n=47) or 1 mg/0.5 mg oral E2/NETA (n = 43). 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 1+2 (F1+2) 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. CONCLUSIONS Compared with oral E2/NETA therapy, intranasal administration of E2/NET had less effect on APC resistance and on a number of other parameters associated with venous thrombosis. This observation suggests the possibility of a lower venous thrombosis risk for intranasal E2/NET compared with oral therapy.