Divergent Effects of Estradiol Regimens on Protein S and Global Coagulation in Transgender Women: A Prospective Pilot...

Sublingual estradiol is increasingly used for gender-affirming hormone therapy (GAHT), but its chronic hemostatic effects remain insufficiently characterized.

To compare hemostatic changes between oral estradiol plus cyproterone acetate (CPA) with divided-dose sublingual estradiol monotherapy in treatment-naive transgender women.

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.

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.

The two GAHT protocols were associated with distinct laboratory hemostatic patterns, suggesting that different GAHT regimens should not be considered hemostatically equivalent. These findings warrant further evaluation in larger studies.