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

NCT07145281 | Completed

• 2 other identifiers: 0388-22-TLVMOH_2022-10-11_012120
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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

Conditions

Gender Dysphoria, Adult; Blood Coagulation; Coagulation Factors; Transgender Persons, M01.777.500; Hemostasis; Transgender Women

Keywords

Transgender women; sublingual estradiol; procoagulant effect; Protein S; Thrombin generation assay (TGA); Gender-affirming hormone therapy (GAHT)

Outcome Measures

Primary Outcomes (1)

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

  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.

  Baseline and 6 months after initiation of therapy

Secondary Outcomes (9)

• Change in Protein C from baseline to 6 months

  Baseline and 6 months after initiation of therapy

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

  Baseline and 6 months after initiation of therapy

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

  Baseline and 6 months after initiation of therapy

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

  Baseline and 6 months after initiation of therapy

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

  Baseline and 6 months after initiation of therapy

Study Arms (2)

Sublingual Estradiol

EXPERIMENTAL

Participants receive sublingual estradiol 2 mg per day divided into 4 doses, without an anti-androgen, for 6 months.

Drug: Estradiol (E2)

Oral Estradiol + Cyproterone Acetate (CPA)

ACTIVE COMPARATOR

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.

Drug: Estradiol (E2); Drug: Cyproterone Acetate (Androcur, BAY94-8367)

Interventions

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.

Also known as: Estrofem

Oral Estradiol + Cyproterone Acetate (CPA); Sublingual Estradiol

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.

Oral Estradiol + Cyproterone Acetate (CPA)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Gender Eligibility Details: Self-identified transgender women (individuals assigned male at birth who identify as female) were eligible to participate in this study. Eligibility was limited to this gender identity.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Tel-Aviv Sourasky Medical Center: lead

Study Sites (1)

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

Tel Aviv, Israel

Location

Related Publications (27)

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MeSH Terms

Conditions

Gender Dysphoria; Thrombosis

Interventions

Estradiol; estradiol, estriol drug combination; Cyproterone Acetate

Condition Hierarchy (Ancestors)

Sexual Dysfunctions, Psychological; Mental Disorders; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Cyproterone; Pregnadienes; Pregnanes; Steroids, Chlorinated

Study Officials

• Iris Yaish, MD

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: IRB Head

Study Record Dates

• First Submitted: August 20, 2025
• First Posted: August 28, 2025
• Study Start: November 10, 2022
• Primary Completion: November 10, 2024
• Study Completion: November 10, 2024
• Last Updated: August 28, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Time Frame: The individual participant data (IPD) set is already available and was uploaded to the Open Science Framework (OSF) repository. The data will remain accessible indefinitely unless otherwise specified in the repository.
• Access Criteria: All researchers will be able to access the de-identified individual participant data (IPD) through the Open Science Framework (OSF) repository. The dataset includes baseline characteristics, laboratory results, and hemostatic parameters collected throughout the 6-month study period. Access is open and unrestricted via the following link: https://doi.org/10.17605/OSF.IO/TCRUW . No registration or approval process is required.

Locations

IL (1)