Coagulation and Fibrinolysis of Estradiol in Transwomen

Study Overview
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Brief Summary
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The specific aim for our study is to measure coagulation system activation and fibrinolysis following transdermal versus sublingual versus oral estradiol versus in transgender women. Hypothesis: Transdermal estradiol will result in less coagulation system activation and no effect on plasminogen activator inhibitor (PAI-1) or tissue-type plasminogen activator (t-PA). Oral estradiol will result in the most coagulation system activation and effect on PAI-1 and t-PA: Oral estradiol > sublingual estradiol > transdermal estradiol. A prospective crossover study will include ten subjects given estradiol 1 mg daily and instructed to take it orally, sublingually, or transdermal for 2 months with a 2-week washout period between routes of administration. Labs will be measured 7 times during the study.

Detailed Description
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Subjects will report to our Adult Translational Research Unit for labs at baseline (2 weeks after HRT washout if needed). Both fibrinolysis and testosterone labs have a diurnal variation. Therefore, fasting labs will be drawn at approximately 8 AM. Five subjects will start oral estradiol and 5 will start sublingual estradiol for 8 weeks. Froedtert's Pharmacy Investigational Drug Service will provide the study estradiol. There will be a 2-week washout period between treatment periods. Fasting labs will be drawn at approximately 8 AM prior to Treatment Period 2. The groups will switch therapy. Those that took oral estradiol during Treatment Period 1 will take sublingual estradiol for 8 weeks. Those that took sublingual estradiol during Treatment Period 1 will take oral estradiol for 8 weeks. Finally, all subjects will start the transdermal for 8 weeks for Treatment Period 3. Final set of labs will be drawn at approximately 8 AM 2 weeks after Treatment Period 3. The investigators will call subjects every 2 weeks to assess their adherence to the treatment protocol and remind them of the importance of allowing the tablet to dissolve when taking estradiol sublingually.

Official Title
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Coagulation Activation and Fibrinolysis With Sublingual Versus Oral Versus Transdermal Estradiol in Transgender Women

Conditions
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Transgenderism, Clotting Disorder

Intervention / Treatment
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* Drug: Estradiol Tablets
* Drug: Transdermal patch
* Drug: Estradiol Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older Gender identity of male to female or transwoman Exclusion Criteria: Liver disease History of blood clot Bleeding disorder Active or recent (e.g., within the past year) stroke Myocardial infarction, History of orchiectomy History of breast cancer, Known sensitivity or allergy to any components of the medications used Currently taking a potent CYP3A4 inhibitor or inducer.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sublingual Estradiol<br>Sublingual estradiol administered for 8 weeks | Drug: Estradiol Tablets<br>* Oral estradiol will be taken sublingually, 1 mg BID for 8 weeks<br>* Other names: Sublingual estradiol tablets;|
| Active Comparator: Oral Estradiol<br>Oral estradiol administered for 8 weeks | Drug: Estradiol Tablets<br>* Oral estradiol 1 mg BID for 8 weeks<br>* Other names: Oral Estradiol tablets;|
| Active Comparator: Transdermal Estradiol<br>Transdermal estradiol administered for 8 weeks | Drug: Transdermal patch<br>* Estradiol patch therapy for 8 weeks<br>* Other names: Transdermal estradiol patch;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coagulation system activation and fibrinolysis due to estradiol administration | Comparison of morning fasting labs (fibrinogen, von-Willebrand Factor (vWF) ristocetin cofactor, vWF antigen, D-dimer, protein C activity, free protein S activity, Factors VII, VIII, IX, thrombin generation, plasminogen activator inhibitor (PAI-1), tissue-type plasminogen activator (t-PA) and t-PA activity) in transgender women taking estradiol via different routes of administration. Our hypothesis is that transdermal estradiol will result in less coagulation system activation and no effect on PAI-1 or t-PA. Oral estradiol will result in the most coagulation system activation and will effect PAI-1 and t-PA: Oral estradiol > sublingual estradiol > transdermal estradiol. | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombotic risk due to estradiol administration | Thrombotic risk will be assessed in transgender women by measuring estrone and thrombin generation and comparing them between the different routes of estradiol administration (transdermal versus sublingual versus oral). | 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Estrogens, Estradiol, Hormones, Hormones, Hormone Substitutes, Hormone Antagonists, Physiological Effects of Drugs, Transgender