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Completed

NCT Number: NCT07145281

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

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

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Key information

Conditions

Gender Dysphoria, Adult Blood Coagulation Cardiovascular Diseases Coagulation Factors Embolism and Thrombosis Gender Dysphoria Hemostasis Mental Disorders Sexual Dysfunctions, Psychological Thrombosis Transgender Persons, M01.777.500 Transgender Women Vascular Diseases

Age range

18 year–45 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Tel Aviv Sourasky Medical Center - Institute of Endocrinology, Metabolism and Hypertension

Tel Aviv, Israel

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Estradiol (E2)

Drug

Participants receive estradiol 2 mg/day. In the experimental arm, estradiol is administered sublingually in four divided doses (0.5 mg each).

In the active comparator arm, estradiol is administered orally, in combination with cyproterone acetate, for 6 months.

All participants are treatment-naive.

Other names: Estrofem

Cyproterone Acetate (Androcur, BAY94-8367)

Drug

Participants in the active comparator arm receive cyproterone acetate (CPA) 10 mg orally, once daily, in combination with oral estradiol, for 6 months.

All participants are treatment-naive.

Primary outcomes

  1. Change from Baseline in Plasma Free Protein S Antigen Concentration at 6 Months

    Time frame: 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 outcomes

  1. Change in Protein C from baseline to 6 months

    Time frame: 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.

  2. Change in Prothrombin Time (PT) from baseline to 6 months

    Time frame: 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.

  3. Change from Baseline in Partial Thromboplastin Time (PTT) at 6 Months

    Time frame: 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

  4. Change from Baseline in International Normalized Ratio (INR) at 6 Months

    Time frame: 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.

  5. Change from Baseline in Thromboelastography (TEG) Reaction Time (R Time) at 6 Months

    Time frame: 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.

  6. Change from Baseline in Thromboelastography (TEG) Maximum Amplitude (MA) at 6 Months

    Time frame: 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.

  7. Change from Baseline in Thrombin Generation Assay (TGA) Lag Time at 6 Months

    Time frame: 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.

  8. Change from Baseline in Thrombin Generation Assay (TGA) Peak Thrombin at 6 Months

    Time frame: 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.

  9. Change from Baseline in Thrombin Generation Assay (TGA) Area Under the Curve (AUC) at 6 Months

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Tel-Aviv Sourasky Medical Center

Other Gov

Registry information

Important dates

Study start
2022
Primary completion
2024
Study completion
2024
First posted
Aug 28, 2025
Registry last updated
Aug 28, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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