Divergent Effects of Estradiol Regimens on Protein S and Global Coagulation in Transgender Women.

BACKGROUND: Sublingual estradiol is increasingly used for gender-affirming hormone therapy (GAHT), but its chronic hemostatic effects remain insufficiently characterized. OBJECTIVES: To compare hemostatic changes between oral estradiol plus cyproterone acetate (CPA) with divided-dose sublingual estradiol monotherapy in treatment-naive transgender women. METHODS: In this prospective, non-randomized study, 30 treatment-naïve transgender women received oral estradiol 2 mg once daily plus CPA 10 mg daily (n=15) or sublingual estradiol 0.5 mg four times daily without an anti-androgen (n=15) for 6 months. Free Protein S antigen, Protein C, thrombin generation assay (TGA), and thromboelastography (TEG) were assessed at baseline and 6 months. RESULTS: Free Protein S antigen decreased in all participants receiving sublingual estradiol (median change, -22%; p<0.001), compared with a smaller, heterogeneous change with oral estradiol plus CPA (median change, -4.2%; p=0.099). At 6 months, median free Protein S antigen was 77% versus 106%, respectively (p=0.003). After adjustment for baseline Protein S and age, sublingual treatment remained associated with lower 6-month levels (B=-15.8; p<0.001). TGA lag time decreased by a median of 19% in the sublingual group, but the between-group difference was not significant after correction (adjusted p=0.063).TEG maximum amplitude increased modestly with oral estradiol plus CPA and differed between groups after correction (adjusted p=0.009), although values remained within physiological ranges. No thrombotic events occurred. CONCLUSIONS: The two GAHT protocols were associated with different laboratory hemostatic patterns, including a reduction in free Protein S antigen with sublingual estradiol. These findings warrant further evaluation in larger mechanistic studies.