VTE risk in transgender women on estrogen therapy: A review of formulation-specific risks, management strategies, and evidence gaps

Abstract Background: Transgender women benefit significantly from gender-affirming hormone therapy (GAHT), particularly estrogen, which improves psychological well-being and reduces gender dysphoria. However, the thrombotic risk associated with estrogen therapy, and its different formulations, especially in high-risk groups, remains unclear due to conflicting literature, heterogeneous study populations, and limited high-quality data. Objectives: To review and discuss the risks of venous thrombosis associated with different hormone replacement therapy (HRT) formulations, their interaction with patient-specific factors, prophylaxis, and treatment considerations for specific high-risk groups. Methods: We conducted a narrative review of the available literature across PubMed, Cochrane, and Google Scholar on VTE events in the context of GAHT in transgender women. Discussion: Compared to transdermal formulations, oral estrogen induces a marked procoagulant shift that includes increased APC (Activated protein C) resistance, elevated factors IX and XI, prothrombin–thrombin fragments, and reduced levels of protein C, protein S, antithrombin, and TFPI (Tissue factor pathway inhibitor) likely due to its molecular structure and are associated with higher incidence of VTE especially in high risk groups (Age > 60 years, obesity, smoking, cardiovascular disease, prior history of VTE, active malignancy, immobility, factor V Leiden, antithrombin deficiency, and other thrombophilic conditions). Current guidelines recommend transdermal 17β-estradiol over oral formulations and to avoid high-risk formulations like ethinyl estradiol and cyproterone acetate. Routine thrombophilia screening is not recommended before initiating hormone therapy, as clinical risk factors offer higher predictive value, and primary prophylaxis with anticoagulation is not indicated in patients on GAHT. In transgender females, discontinuation of gender-affirming hormone therapy (GAHT) following a VTE event can lead to significant emotional and psychological distress. As a result, recent studies support continuing GAHT preferably at a reduced dose while initiating therapeutic anticoagulation, with extended or indefinite duration, which should be considered through shared decision-making, after weighing risks, benefits, and patient preferences to balance thrombotic risk with gender dysphoria and overall well-being. A meta-analysis of nine clinical trials showed that the risk of VTE is highest in the first year of hormone therapy (OR 4.0, 95% CI: 2.9–5.7), which attenuates later but remains elevated (OR 2.1, 95% CI: 1.3–3.8). No significant difference in VTE risk was found between unopposed (OR 2.2, 95% CI: 1.6–3.0) and opposed oral estrogen (OR 2.6, 95% CI: 2.0–3.2). In the perioperative setting, continuation of hormone therapy or decreased dose in high-risk groups with standard VTE prophylaxis, guided by Caprini scoring, is recommended as no increase in postoperative VTE was observed in multiple retrospective cohorts and meta-analyses. Although VTE events are rare, transgender patients with personal or family histories of VTE are often referred to haematologists, highlighting the importance of clinician familiarity with different formulations of GAHT and its thrombotic risks. Conclusions: Clinicians should consider hormone type, dose, route, and individual thrombotic risk when initiating HRT in transgender women. A personalized approach is crucial for minimizing the risk of VTE. Further research is needed to evaluate routine anticoagulation prophylaxis in high-risk patients starting HRT or GAHT, including prospective VTE risk models specific to hormone therapy formulations and high-risk groups. Additionally, randomized trials are necessary to compare perioperative continuation versus cessation of hormones. Additionally, the long-term outcomes of extended anticoagulation in patients requiring ongoing hormone therapy remain unknown, necessitating further studies in this area.