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

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

Timeline

Start

2022-11-10

Primary completion

2024-11-10

Completion

2024-11-10

Publications

• Results 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.
• Results 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.
• Results 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.
• Results American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Association; 2013.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results Asscheman H, Gooren LJ, Eklund PL. Mortality and morbidity in transsexual patients with cross-gender hormone treatment. Metabolism. 1989 Sep;38(9):869-73. doi: 10.1016/0026-0495(89)90233-3.
• Results 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.
• Results 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.
• Results Eisenberger A, Westhoff C. Hormone replacement therapy and venous thromboembolism. J Steroid Biochem Mol Biol. 2014 Jul;142:76-82. doi: 10.1016/j.jsbmb.2013.08.016. Epub 2013 Sep 3.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.

Drugs

Indications