Comparing the Effects of Sublingual Estradiol Treatment Versus Oral Estradiol With Cyproterone Acetate (CPA) Treatment on The Coagulation System in Transgender Women: A Prospective, Controlled Cohort Study

Not Applicable

Completed

• Conditions: Gender Dysphoria, Adult; Blood Coagulation; Coagulation Factors; Transgender Persons, M01.777.500; Hemostasis; Transgender Women
• Interventions: Drug: Estradiol (E2); Drug: Cyproterone Acetate (Androcur, BAY94-8367)

• Registration Number: NCT07145281
• Lead Sponsor: Tel-Aviv Sourasky Medical Center

Brief Summary

The goal of this clinical trial is to learn about the effects of different routes of estradiol administration on blood clotting in transgender women starting gender-affirming hormone therapy. The main questions it aims to answer are:

Does sublingual estradiol reduce free Protein S levels compared to oral estradiol with cyproterone acetate?

Does sublingual estradiol accelerate activation of the clotting system, as measured by thrombin generation?

Researchers will compare sublingual estradiol to oral estradiol plus cyproterone acetate to see if the way estradiol is taken changes blood clotting risk.

Participants will:

Take either sublingual estradiol (2 mg daily in divided doses) or oral estradiol (2 mg daily) with cyproterone acetate (10 mg daily) for 6 months

Provide blood samples at baseline and after 6 months to measure hormone levels and clotting factors

Attend clinic visits for monitoring, including safety checks and routine laboratory tests

Detailed Description

Not available

Study Timeline

• Study Start: 2022-11-10
• Primary Completion: 2024-11-10
• Study Completion: 2024-11-10
• Status Verified: 2025-08
• Study First Submitted: 2025-08-20
• Study First Submitted QC: 2025-08-20
• Last Update Submitted: 2025-08-20
• Study First Posted: 2025-08-28
• Last Update Posted: 2025-08-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 30

Inclusion Criteria

• Self-identified transgender women
• Aged 18 to 45 years
• Healthy individuals
• Treatment-naïve (not previously exposed to gender-affirming hormone therapy)
• Presenting for gender-affirming hormone therapy (GAHT)
• Provided written informed consent

Exclusion Criteria

• Active smokers
• Personal or family history of venous thromboembolism (VTE) or thrombophilia
• History of malignancy in the past 5 years
• Chronic liver disease
• Chronic kidney disease
• Hyperlipidemia

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sublingual Estradiol	Estradiol (E2)	Participants receive sublingual estradiol 2 mg per day divided into 4 doses, without an anti-androgen, for 6 months.
Oral Estradiol + Cyproterone Acetate (CPA)	Estradiol (E2)	Participants receive oral estradiol 2 mg once daily combined with cyproterone acetate 10 mg once daily for 6 months. This represents the standard regimen used in routine care.
Oral Estradiol + Cyproterone Acetate (CPA)	Cyproterone Acetate (Androcur, BAY94-8367)	Participants receive oral estradiol 2 mg once daily combined with cyproterone acetate 10 mg once daily for 6 months. This represents the standard regimen used in routine care.

Primary Outcome Measures

Name	Time	Method
Change from Baseline in Plasma Free Protein S Antigen Concentration at 6 Months	Baseline and 6 months after initiation of therapy	Plasma concentration of free Protein S antigen will be measured at baseline and after 6 months of treatment. A reduction of ≥20% in free Protein S is anticipated in the sublingual estradiol group, with no comparable change expected in the oral estradiol group.

Secondary Outcome Measures

Name	Time	Method
Change in Protein C from baseline to 6 months	Baseline and 6 months after initiation of therapy	Plasma concentration of Protein C antigen will be measured using immunologic assays at baseline and after 6 months of treatment.
Change in Prothrombin Time (PT) from baseline to 6 months	Baseline and 6 months after initiation of therapy	PT will be measured at baseline and after 6 months using conventional clotting assays to evaluate changes in coagulation function.
Change from Baseline in Partial Thromboplastin Time (PTT) at 6 Months	Baseline and 6 months after initiation of therapy	PTT will be measured at baseline and after 6 months using conventional clotting assays to evaluate changes in intrinsic coagulation pathway function
Change from Baseline in International Normalized Ratio (INR) at 6 Months	Baseline and 6 months after initiation of therapy	INR will be measured at baseline and after 6 months using standard prothrombin time-based assays to assess changes in coagulation status.
Change from Baseline in Thromboelastography (TEG) Reaction Time (R Time) at 6 Months	Baseline and 6 months after initiation of therapy	TEG Reaction Time (R time) will be measured at baseline and after 6 months using thromboelastography. R time is defined as the latency period from the start of the test until initial fibrin formation begins, reflecting the initiation phase of coagulation.
Change from Baseline in Thromboelastography (TEG) Maximum Amplitude (MA) at 6 Months	Baseline and 6 months after initiation of therapy	TEG Maximum Amplitude (MA) will be measured at baseline and after 6 months using thromboelastography. MA reflects the maximum strength of the formed clot and is influenced by platelet function and fibrinogen levels.
Change from Baseline in Thrombin Generation Assay (TGA) Lag Time at 6 Months	Baseline and 6 months after initiation of therapy	Lag time in the thrombin generation assay will be measured at baseline and after 6 months. TGA lag time represents the time until the initiation of thrombin generation, reflecting the onset of the coagulation process.
Change from Baseline in Thrombin Generation Assay (TGA) Peak Thrombin at 6 Months	Baseline and 6 months after initiation of therapy	Peak thrombin levels will be measured using thrombin generation assay at baseline and after 6 months. This metric represents the highest concentration of thrombin generated during the assay and reflects the overall procoagulant potential.
Change from Baseline in Thrombin Generation Assay (TGA) Area Under the Curve (AUC) at 6 Months	Baseline and 6 months after initiation of therapy	The area under the curve (AUC) in the thrombin generation assay will be calculated at baseline and after 6 months. AUC reflects the total amount of thrombin generated over time, providing a global measure of thrombin-generating capacity.

Trial Locations

Locations (1)

Tel Aviv Sourasky Medical Center - Institute of Endocrinology, Metabolism and Hypertension; 🇮🇱 Tel Aviv, Israel