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Gender Dysphoria, AdultNCT07145281

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

A study testing Estradiol (E2) and Cyproterone Acetate (Androcur, BAY94-8367) in people with Gender Dysphoria, Adult and Blood Coagulation, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 45 years, men onlyHealthy volunteers can take part
What is being tested?
Estradiol (E2) and Cyproterone Acetate (Androcur, BAY94-8367)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteIsrael
Study dates
10 Nov 2022to 10 Nov 2024
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 45 years
  • Men only
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

Israel1 site

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

    Tel Aviv

Other trials in Israel

About this 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?

Read more

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

Being tested
Estradiol (E2), Cyproterone Acetate (Androcur, BAY94-8367)
Keywords
Transgender women, sublingual estradiol, procoagulant effect, Protein S, Thrombin generation assay (TGA), Gender-affirming hormone therapy (GAHT)
Medical subject headings
Gender Dysphoria, Thrombosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Estradiol (E2)Drug

    Also called Estrofem

    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.

  • 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.

Study groups in NCT07145281
Study groupRoleWhat they receive
Sublingual EstradiolExperimentalParticipants receive sublingual estradiol 2 mg per day divided into 4 doses, without an anti-androgen, for 6 months.
Receives: Drug: Estradiol (E2)
Oral Estradiol + Cyproterone Acetate (CPA)Active comparatorParticipants 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.
Receives: Drug: Estradiol (E2); Drug: Cyproterone Acetate (Androcur, BAY94-8367)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline and 6 months after initiation of therapy

Secondary outcomes (9)

  1. Change in Protein C from baseline to 6 months

    Plasma concentration of Protein C antigen will be measured using immunologic assays at baseline and after 6 months of treatment.

    Measured: Baseline and 6 months after initiation of therapy

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

    PT will be measured at baseline and after 6 months using conventional clotting assays to evaluate changes in coagulation function.

    Measured: Baseline and 6 months after initiation of therapy

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

    PTT will be measured at baseline and after 6 months using conventional clotting assays to evaluate changes in intrinsic coagulation pathway function

    Measured: Baseline and 6 months after initiation of therapy

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

    INR will be measured at baseline and after 6 months using standard prothrombin time-based assays to assess changes in coagulation status.

    Measured: Baseline and 6 months after initiation of therapy

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

    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.

    Measured: Baseline and 6 months after initiation of therapy

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

    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.

    Measured: Baseline and 6 months after initiation of therapy

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

    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.

    Measured: Baseline and 6 months after initiation of therapy

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

    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.

    Measured: Baseline and 6 months after initiation of therapy

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

    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.

    Measured: Baseline and 6 months after initiation of therapy

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Aug 2025
  2. Study start10 Nov 2022
  3. Primary completion10 Nov 2024
  4. Study completion10 Nov 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07145281
Sponsor's protocol ID
0388-22-TLV
Other IDs
MOH_2022-10-11_012120
Status last verified
Aug 2025
First submitted
20 Aug 2025
Last updated
28 Aug 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: All de-identified individual participant data (IPD), including baseline characteristics, hormonal and metabolic parameters, and hemostatic assay results collected during the 6-month intervention period, will be shared via the Open Science Framework repository (DOI: 10.17605/OSF.IO/TCRUW).

Publications

  • Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017 Nov 1;102(11):3869-3903. doi: 10.1210/jc.2017-01658.

    PubMed 28945902

  • Dhejne C, Van Vlerken R, Heylens G, Arcelus J. Mental health and gender dysphoria: A review of the literature. Int Rev Psychiatry. 2016;28(1):44-57. doi: 10.3109/09540261.2015.1115753.

    PubMed 26835611

  • Ali-Saleh M, Sarig G, Ablin JN, Brenner B, Jacob G. Inhalation of a Short-Acting beta2-Adrenoreceptor Agonist Induces a Hypercoagulable State in Healthy Subjects. PLoS One. 2016 Jul 5;11(7):e0158652. doi: 10.1371/journal.pone.0158652. eCollection 2016.

    PubMed 27379911

  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Association; 2013.

  • Even Zohar N, Sofer Y, Yaish I, Serebro M, Tordjman K, Greenman Y. Low-Dose Cyproterone Acetate Treatment for Transgender Women. J Sex Med. 2021 Jul;18(7):1292-1298. doi: 10.1016/j.jsxm.2021.04.008. Epub 2021 Jun 24.

    PubMed 34176757

  • Connors JM, Middeldorp S. Transgender patients and the role of the coagulation clinician. J Thromb Haemost. 2019 Nov;17(11):1790-1797. doi: 10.1111/jth.14626. Epub 2019 Sep 13.

    PubMed 31465627

  • Dupuis M, Severin S, Noirrit-Esclassan E, Arnal JF, Payrastre B, Valera MC. Effects of Estrogens on Platelets and Megakaryocytes. Int J Mol Sci. 2019 Jun 25;20(12):3111. doi: 10.3390/ijms20123111.

    PubMed 31242705

  • Yokota N, Inoue R, Kawamura K, Egashira K, Kuma H, Kato K. The effects of dienogest and combined oral contraceptives on protein S-specific activity in endometriosis patients. Eur J Obstet Gynecol Reprod Biol. 2024 Apr;295:67-74. doi: 10.1016/j.ejogrb.2024.01.028. Epub 2024 Jan 29.

    PubMed 38340593

  • Mihaila RG, Catana C, Olteanu AL, Birlutiu V, Salcudean C, Mihaila MD. Thrombin generation is increased in patients with Clostridium difficile colitis - a pilot study. Biomarkers. 2019 Jun;24(4):389-393. doi: 10.1080/1354750X.2019.1600021. Epub 2019 Apr 9.

    PubMed 30907672

  • Volod O, Runge A. The TEG 5000 System: System Description and Protocol for Measurements. Methods Mol Biol. 2023;2663:725-733. doi: 10.1007/978-1-0716-3175-1_48.

    PubMed 37204748

  • Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab. 2003 Dec;88(12):5723-9. doi: 10.1210/jc.2003-030520.

    PubMed 14671159

  • van Ommen CH, Fijnvandraat K, Vulsma T, Delemarre-Van De Waal HA, Peters M. Acquired protein S deficiency caused by estrogen treatment of tall stature. J Pediatr. 1999 Oct;135(4):477-81. doi: 10.1016/s0022-3476(99)70171-x.

    PubMed 10518082

  • Raps M, Helmerhorst FM, Fleischer K, Dahm AE, Rosendaal FR, Rosing J, Reitsma P, Sandset PM, van Vliet HA. The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI. Thromb Haemost. 2013 Apr;109(4):606-13. doi: 10.1160/TH12-10-0771. Epub 2013 Feb 14.

    PubMed 23407778

  • Majumder R, Nguyen T. Protein S: function, regulation, and clinical perspectives. Curr Opin Hematol. 2021 Sep 1;28(5):339-344. doi: 10.1097/MOH.0000000000000663.

    PubMed 34224431

  • Bogehave M, Glintborg D, Christensen LL, T'Sjoen G, Vervalcke J, Wiepjes CM, den Heijer M, Andersen MS, Bladbjerg EM. The thrombin generation potential increases after feminizing gender-affirming hormone treatment, decreases after masculinizing gender-affirming hormone treatment, and is determined by the hormone treatment regimen. J Thromb Haemost. 2025 Oct;23(10):3084-3097. doi: 10.1016/j.jtha.2025.03.006. Epub 2025 Mar 14.

    PubMed 40090622

Questions about this trial

What is this clinical trial studying?

A study testing Estradiol (E2) and Cyproterone Acetate (Androcur, BAY94-8367) in people with Gender Dysphoria, Adult and Blood Coagulation, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change from Baseline in Plasma Free Protein S Antigen Concentration at 6 Months (time frame: Baseline and 6 months after initiation of therapy). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07145281, which also lists 27 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Aug 2025.

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