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| ID | Type | Description | Link |
|---|---|---|---|
| MOH_2022-10-11_012120 | Other Identifier | Israel Ministry of Health |
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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sublingual Estradiol | Experimental | Participants receive sublingual estradiol 2 mg per day divided into 4 doses, without an anti-androgen, for 6 months. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline and 6 months after initiation of therapy |
| Change in Prothrombin Time (PT) from baseline to 6 months |
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Inclusion Criteria:
Exclusion Criteria:
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.
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| Name | Affiliation | Role |
|---|---|---|
| Iris Yaish, MD | Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tel Aviv Sourasky Medical Center - Institute of Endocrinology, Metabolism and Hypertension | Tel Aviv | Israel |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28945902 | Result | 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. | |
| 26835611 |
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| ID | Type | URL | Comment |
|---|---|---|---|
| Individual Participant Data Set | View IPD |
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).
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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.
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.
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| 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. |
|
PT will be measured at baseline and after 6 months using conventional clotting assays to evaluate changes in coagulation function. |
| Baseline and 6 months after initiation of therapy |
| 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 | Baseline and 6 months after initiation of therapy |
| 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. | Baseline and 6 months after initiation of therapy |
| 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. | Baseline and 6 months after initiation of therapy |
| 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. | Baseline and 6 months after initiation of therapy |
| 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. | Baseline and 6 months after initiation of therapy |
| 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. | Baseline and 6 months after initiation of therapy |
| 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. | Baseline and 6 months after initiation of therapy |
| 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. |
| 27379911 | Result | 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. |
| Result | American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Association; 2013. |
| 34176757 | Result | 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. |
| 31465627 | Result | 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. |
| 31242705 | Result | 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. |
| 38340593 | Result | 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. |
| 30907672 | Result | 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. |
| 37204748 | Result | 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. |
| 14671159 | Result | 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. |
| 10518082 | Result | 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. |
| 23407778 | Result | 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. |
| 34224431 | Result | 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. |
| 40090622 | Result | 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. |
| 32413907 | Result | Lim HY, Leemaqz SY, Torkamani N, Grossmann M, Zajac JD, Nandurkar H, Ho P, Cheung AS. Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy. J Clin Endocrinol Metab. 2020 Jul 1;105(7):dgaa262. doi: 10.1210/clinem/dgaa262. |
| 33527671 | Result | Scheres LJJ, Selier NLD, Nota NM, van Diemen JJK, Cannegieter SC, den Heijer M. Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen. J Thromb Haemost. 2021 Apr;19(4):1029-1037. doi: 10.1111/jth.15256. Epub 2021 Feb 22. |
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| 30776252 | Result | Nota NM, Wiepjes CM, de Blok CJM, Gooren LJG, Kreukels BPC, den Heijer M. Occurrence of Acute Cardiovascular Events in Transgender Individuals Receiving Hormone Therapy. Circulation. 2019 Mar 12;139(11):1461-1462. doi: 10.1161/CIRCULATIONAHA.118.038584. No abstract available. |
| 27916515 | Result | Tangpricha V, den Heijer M. Oestrogen and anti-androgen therapy for transgender women. Lancet Diabetes Endocrinol. 2017 Apr;5(4):291-300. doi: 10.1016/S2213-8587(16)30319-9. Epub 2016 Dec 2. |
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| 34781041 | Result | Doll E, Gunsolus I, Thorgerson A, Tangpricha V, Lamberton N, Sarvaideo JL. Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women. Endocr Pract. 2022 Mar;28(3):237-242. doi: 10.1016/j.eprac.2021.11.081. Epub 2021 Nov 13. |
| 32926454 | Result | Angus LM, Nolan BJ, Zajac JD, Cheung AS. A systematic review of antiandrogens and feminization in transgender women. Clin Endocrinol (Oxf). 2021 May;94(5):743-752. doi: 10.1111/cen.14329. Epub 2020 Oct 5. |
| 33251587 | Result | Haupt C, Henke M, Kutschmar A, Hauser B, Baldinger S, Saenz SR, Schreiber G. Antiandrogen or estradiol treatment or both during hormone therapy in transitioning transgender women. Cochrane Database Syst Rev. 2020 Nov 28;11(11):CD013138. doi: 10.1002/14651858.CD013138.pub2. |
| 26276103 | Result | Canonico M. Hormone therapy and risk of venous thromboembolism among postmenopausal women. Maturitas. 2015 Nov;82(3):304-7. doi: 10.1016/j.maturitas.2015.06.040. Epub 2015 Jul 26. |
| 12763518 | Result | Peverill RE. Hormone therapy and venous thromboembolism. Best Pract Res Clin Endocrinol Metab. 2003 Mar;17(1):149-64. doi: 10.1016/s1521-690x(02)00079-9. |
| 38130980 | Result | Yaish I, Gindis G, Greenman Y, Moshe Y, Arbiv M, Buch A, Sofer Y, Shefer G, Tordjman K. Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study. Transgend Health. 2023 Dec 13;8(6):485-493. doi: 10.1089/trgh.2023.0022. eCollection 2023 Dec. |
| ID | Term |
|---|---|
| D000068116 | Gender Dysphoria |
| D013927 | Thrombosis |
| ID | Term |
|---|---|
| D020018 | Sexual Dysfunctions, Psychological |
| D001523 | Mental Disorders |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D004958 | Estradiol |
| C044003 | estradiol, estriol drug combination |
| D017373 | Cyproterone Acetate |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D003534 | Cyproterone |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013258 | Steroids, Chlorinated |
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