Transgender Estradiol Affirming Therapy

Study Overview
=================
Brief Summary
-----------------
The purpose of this open label, pilot, randomized clinical trial is to evaluate the effectiveness, safety and tolerability of estrogen use in transgender female and the degree of testosterone suppression achieved in this population when placed on gender affirming pharmacological therapy.

Detailed Description
-----------------
Transgender patients suffer from poor mental and medical health outcomes compared to their cisgender peers. Given the widespread acknowledgment of the health care needs of transgender people, priority should be given to those actions that will ensure safe and appropriate care in health centers. The current hormone therapy is not uniform and depends on the health care system, cost considerations, and differences in the regional availability of estrogens and antiandrogens. A typical regimen includes estrogen to provide feminizing effects in conjunction with therapy to block testosterone (antiandrogens or gonadotropin-releasing hormone [GnRH] analogs). Estrogen also inhibits testosterone secretion. Ethinyl estradiol was previously the mainstay of most estrogen-directed therapies; this is no longer the case due to its increased risk of cardiovascular death and increased incidence of deep venous thrombosis. 17-beta estradiol, which can be provided in tablet, patch, and injection, is currently the preferred formulation. This open label, pilot, randomized clinical trial will evaluate the effectiveness and safety of gender affirming hormone therapy with estrogen and the degree of testosterone suppression achieved in transgender female patients when placed on daily sublingual 17-beta estradiol, twice daily sublingual 17-beta estradiol, or transdermal 17-beta estradiol. All patients will also receive spironolactone as antiandrogen. One of the major complications from estradiol GAHT is thromboembolism. The investigators will also determine the effects of the different estradiol regimens on thrombosis markers. These studies will be the first to determine if the dosing regimen of estradiol affects risk markers in transgender women.

Official Title
-----------------
Effectiveness and Safety of Different Estradiol Replacement Therapies in Transgender Female

Conditions
-----------------
Transgenderism

Intervention / Treatment
-----------------
* Drug: Transdermal patch
* Diagnostic Test: Pro-thrombotic markers
* Diagnostic Test: Metabolic markers
* Diagnostic Test: Hormone Profile
* Drug: Sublingual Tablet
* Drug: Sublingual Tablet
* Drug: Spironolactone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female transgender patients between the ages of 18 to 30 years of age who are seen at the Washington University Transgender Center. Patients must have met the eligibility and readiness criteria for gender-affirming hormone therapy. Exclusion Criteria: GnRH agonist for the last 12 months History of liver disease Dyslipidemia requiring treatment Cigarette smoking Body mass index >30 kg/m2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants who agreed to be in the study will undergo block randomization into three groups: daily sublingual 17 beta estradiol twice daily sublingual 17 beta estradiol transdermal 17 beta estradiol All patients will also receive spironolactone as antiandrogen.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Transdermal estradiol plus spironolactone<br>Starting dose will be 100 mcg/24hrs Plan to increase by 100 mcg/24hrs every month to a max dose of 400 mcg/24hrs Goal is to achieve a serum estradiol level between 100-200 pg/mL and to suppress testosterone to cisgender female levels All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose. | Drug: Transdermal patch<br>* Participants will be prescribed the medication and dosed based on their hormonal profile. Goal is achieve estradiol level between 100-200 pg/mL and to suppress testosterone to cisgender female levels<br>Diagnostic Test: Pro-thrombotic markers<br>* Once participants are started on gender affirming hormone therapy, pro-thombotic markers will be checked at baseline and every 6 months. Pro-thrombotic markers will include: Factor II, Factor IX, Factor XI, Von Willebrand factor, Protein C, Protein S, activated Protein C resistance.<br>Diagnostic Test: Metabolic markers<br>* Once participants are started on gender affirming hormone therapy, metabolic markers will be checked at baseline and every 6 months. Markers will include: Insulin level, fasting glucose, body mass index, waist circumference.<br>Diagnostic Test: Hormone Profile<br>* Once participants are started on gender affirming hormone therapy, hormonal levels will be checked every 4 weeks until estradiol and testosterone levels are within goal as established by standard of care.<br>Drug: Spironolactone<br>* All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose.<br>|
| Active Comparator: Daily sublingual estradiol plus spironolactone<br>Starting dose will be 2 mg daily Plan to increase every month by 2 mg daily Goal is to achieve serum estradiol level between 100-200 pg/mL mL and to suppress testosterone to cisgender female levels. All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose. Spironolactone will be started at 50 mg daily and will increase to standard dose. | Diagnostic Test: Pro-thrombotic markers<br>* Once participants are started on gender affirming hormone therapy, pro-thombotic markers will be checked at baseline and every 6 months. Pro-thrombotic markers will include: Factor II, Factor IX, Factor XI, Von Willebrand factor, Protein C, Protein S, activated Protein C resistance.<br>Diagnostic Test: Metabolic markers<br>* Once participants are started on gender affirming hormone therapy, metabolic markers will be checked at baseline and every 6 months. Markers will include: Insulin level, fasting glucose, body mass index, waist circumference.<br>Diagnostic Test: Hormone Profile<br>* Once participants are started on gender affirming hormone therapy, hormonal levels will be checked every 4 weeks until estradiol and testosterone levels are within goal as established by standard of care.<br>Drug: Sublingual Tablet<br>* Participants will be prescribed the medication and dosed based on their hormonal profile. Participants will take dose as once daily medication. Goal is achieve estradiol level between 100-200 pg/mL and to suppress testosterone to cisgender female levels<br>* Other names: Once daily dosing;Drug: Spironolactone<br>* All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose.<br>|
| Active Comparator: Twice daily sublingual estradiol plus spironolactone<br>Starting dose will be 1 mg twice daily Plan to increase every month by 2 mg daily divided BID Goal is to achieve serum estradiol level between 100-200 pg/mL mL and to suppress testosterone to cisgender female levels All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose. Spironolactone will be started at 50 mg daily and will increase to standard dose. | Diagnostic Test: Pro-thrombotic markers<br>* Once participants are started on gender affirming hormone therapy, pro-thombotic markers will be checked at baseline and every 6 months. Pro-thrombotic markers will include: Factor II, Factor IX, Factor XI, Von Willebrand factor, Protein C, Protein S, activated Protein C resistance.<br>Diagnostic Test: Metabolic markers<br>* Once participants are started on gender affirming hormone therapy, metabolic markers will be checked at baseline and every 6 months. Markers will include: Insulin level, fasting glucose, body mass index, waist circumference.<br>Diagnostic Test: Hormone Profile<br>* Once participants are started on gender affirming hormone therapy, hormonal levels will be checked every 4 weeks until estradiol and testosterone levels are within goal as established by standard of care.<br>Drug: Sublingual Tablet<br>* Participants will be prescribed the medication and dosed based on their hormonal profile. Participants will take dose as twice daily medication. Goal is achieve estradiol level between 100-200 pg/mL and to suppress testosterone to cisgender female levels<br>* Other names: Twice daily dosing;Drug: Spironolactone<br>* All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Degree of testosterone suppression by measuring total testosterone level in transgender female patients undergoing hormonal affirming therapy |  | Change from baseline total testosterone level at 6,12,18, and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coagulation factors II, IX, XI, Protein C, Protein S, von Willebrand factor, and activated protein C resistance in transgender female patients undergoing |  | Change from baseline factor II, IX, XI, Protein C, Protein S, von Willebrand factor, and activated protein C resistance level at 6,12,18, and 24 months | 
| von Willebrand factor in transgender female patients undergoing |  | Change from baseline von Willebrand factor antigen level at 6,12,18, and 24 months | 
| Llipid panel |  | Changes from baseline lipid panel at 12 and 24 months | 
| Homeostatic Model Assessment for Insulin Resistance |  | Change from baseline HOMA-IR at 6,12,18, and 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Transgender female, Gender affirming hormone therapy, Estrogen therapy