Transgenderism
Conditions
Keywords
Transgender female, Gender affirming hormone therapy, Estrogen therapy
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.
Interventions
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
DIAGNOSTIC_TESTPro-thrombotic markers
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.
DIAGNOSTIC_TESTMetabolic markers
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.
DIAGNOSTIC_TESTHormone Profile
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.
DRUGDaily Sublingual Tablet
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
DRUGBID Sublingual Tablet
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
DRUGSpironolactone
All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants who agreed to be in the study will undergo block randomization into three groups: 1. daily sublingual 17 beta estradiol 2. twice daily sublingual 17 beta estradiol 3. transdermal 17 beta estradiol All patients will also receive spironolactone as antiandrogen.
Eligibility
Sex/Gender
MALE
Age
18 Years to 30 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Testosterone Level in Transgender Female Patients | Change from baseline total testosterone level at 1 and 6 months | Degree of testosterone suppression by measuring total testosterone level in transgender female patients undergoing hormonal affirming therapy, clinical testosterone level in pg/mL |
| Estradiol Level in Transgender Female Patients | Change from baseline estradiol level at 1 and 6 months | Degree of testosterone suppression by measuring estradiol level in transgender female patients affirming hormone therapy |
| Estrone Level in Transgender Female Patients | Change from baseline estrone level at 1, and 6 months | Degree of testosterone suppression by measuring estrone level in transgender female patients affirming hormone therapy |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Transdermal Estradiol Plus Spironolactone 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.
Transdermal patch: 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
Pro-thrombotic markers: 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.
Metabolic markers: 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.
Hormone Profile: 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. | 12 |
| Daily Sublingual Estradiol Plus Spironolactone 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.
Pro-thrombotic markers: 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.
Metabolic markers: 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.
Hormone Profile: 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.
Daily Sublingual Tablet: 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. | 13 |
| Twice Daily Sublingual Estradiol Plus Spironolactone 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.
Pro-thrombotic markers: 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.
Metabolic markers: 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.
Hormone Profile: 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.
BID Sublingual Tablet: 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. | 14 |
| Total | 39 |
Baseline characteristics
| Characteristic | Total | Daily Sublingual Estradiol Plus Spironolactone | Twice Daily Sublingual Estradiol Plus Spironolactone | Transdermal Estradiol Plus Spironolactone |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 13 Participants | 14 Participants | 12 Participants |
| Age, Continuous | 25.3 years | 25.0 years | 21.5 years | 25.3 years |
| Albumin | 4.9 g/dL STANDARD_DEVIATION 0.3 | 4.9 g/dL STANDARD_DEVIATION 0.3 | 4.9 g/dL STANDARD_DEVIATION 0.3 | 4.9 g/dL STANDARD_DEVIATION 0.3 |
| Alkaline phosphatase | 78.4 U/L STANDARD_DEVIATION 20.6 | 75.9 U/L STANDARD_DEVIATION 24 | 77.6 U/L STANDARD_DEVIATION 17 | 82.3 U/L STANDARD_DEVIATION 22.1 |
| ALT | 25.6 U/L STANDARD_DEVIATION 13.7 | 23.2 U/L STANDARD_DEVIATION 9.7 | 24.1 U/L STANDARD_DEVIATION 14.8 | 30.3 U/L STANDARD_DEVIATION 16.2 |
| AST | 23.3 U/L STANDARD_DEVIATION 6.3 | 23.0 U/L STANDARD_DEVIATION 6.4 | 22.2 U/L STANDARD_DEVIATION 6.6 | 25.2 U/L STANDARD_DEVIATION 6 |
| Bicarbonate | 25.1 mmol/L STANDARD_DEVIATION 3.2 | 26.0 mmol/L STANDARD_DEVIATION 2.9 | 25.1 mmol/L STANDARD_DEVIATION 3.5 | 24.2 mmol/L STANDARD_DEVIATION 3.1 |
| Blood urea nitrogen | 13.6 mg/dL STANDARD_DEVIATION 4.3 | 12.5 mg/dL STANDARD_DEVIATION 3.2 | 14.1 mg/dL STANDARD_DEVIATION 5.5 | 14.3 mg/dL STANDARD_DEVIATION 3.7 |
| BMI | 25.1 kg/m^2 STANDARD_DEVIATION 6 | 26.2 kg/m^2 STANDARD_DEVIATION 7.2 | 23.9 kg/m^2 STANDARD_DEVIATION 5 | 25.2 kg/m^2 STANDARD_DEVIATION 5.9 |
| Calcium | 9.7 mg/dL STANDARD_DEVIATION 0.3 | 9.6 mg/dL STANDARD_DEVIATION 0.3 | 9.8 mg/dL STANDARD_DEVIATION 0.3 | 9.7 mg/dL STANDARD_DEVIATION 0.3 |
| Chloride | 102.4 mmol/L STANDARD_DEVIATION 2.2 | 102.9 mmol/L STANDARD_DEVIATION 2.4 | 101.6 mmol/L STANDARD_DEVIATION 2 | 103.0 mmol/L STANDARD_DEVIATION 1.9 |
| Creatinine | 0.9 mg/dL STANDARD_DEVIATION 0.2 | 0.9 mg/dL STANDARD_DEVIATION 0.1 | 0.9 mg/dL STANDARD_DEVIATION 0.2 | 1.0 mg/dL STANDARD_DEVIATION 0.2 |
| Diastolic blood pressure | 86.0 mmHg STANDARD_DEVIATION 9 | 87.5 mmHg STANDARD_DEVIATION 9.7 | 82.1 mmHg STANDARD_DEVIATION 10.4 | 87.9 mmHg STANDARD_DEVIATION 6.7 |
| Estradiol | 25.3 pg/mL STANDARD_DEVIATION 13 | 25.8 pg/mL STANDARD_DEVIATION 10.8 | 23.4 pg/mL STANDARD_DEVIATION 13.5 | 27.1 pg/mL STANDARD_DEVIATION 15.5 |
| Estrone | 30.2 pg/mL STANDARD_DEVIATION 18.7 | 27.7 pg/mL STANDARD_DEVIATION 20.9 | 26.7 pg/mL STANDARD_DEVIATION 14 | 37.2 pg/mL STANDARD_DEVIATION 20.7 |
| Height | 175.9 cm STANDARD_DEVIATION 8.4 | 177.6 cm STANDARD_DEVIATION 9.9 | 176.9 cm STANDARD_DEVIATION 8.4 | 173.5 cm STANDARD_DEVIATION 6.5 |
| Lifestyle Alcohol use | 5 participants | 3 participants | 1 participants | 1 participants |
| Lifestyle Vaping | 2 participants | 0 participants | 2 participants | 0 participants |
| Plasma protein | 7.7 g/dL STANDARD_DEVIATION 0.5 | 7.7 g/dL STANDARD_DEVIATION 0.4 | 7.8 g/dL STANDARD_DEVIATION 0.7 | 7.8 g/dL STANDARD_DEVIATION 0.3 |
| Potassium | 4.1 mmol/L STANDARD_DEVIATION 0.4 | 4.0 mmol/L STANDARD_DEVIATION 0.3 | 4.2 mmol/L STANDARD_DEVIATION 0.5 | 4.0 mmol/L STANDARD_DEVIATION 0.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 32 Participants | 12 Participants | 11 Participants | 9 Participants |
| Region of Enrollment United States | 39 Participants | 13 Participants | 14 Participants | 12 Participants |
| Sex: Female, Male Female | 39 Participants | 13 Participants | 14 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sodium | 139.9 mmol/L STANDARD_DEVIATION 1.8 | 140.4 mmol/L STANDARD_DEVIATION 1.4 | 139.1 mmol/L STANDARD_DEVIATION 1.6 | 140.3 mmol/L STANDARD_DEVIATION 2.1 |
| Systolic blood pressure | 134.0 mmHg STANDARD_DEVIATION 18 | 140.8 mmHg STANDARD_DEVIATION 21.7 | 128.3 mmHg STANDARD_DEVIATION 16.9 | 132.8 mmHg STANDARD_DEVIATION 12.6 |
| Total bilirubin | 0.5 mg/dL STANDARD_DEVIATION 0.3 | 0.5 mg/dL STANDARD_DEVIATION 0.2 | 0.5 mg/dL STANDARD_DEVIATION 0.3 | 0.5 mg/dL STANDARD_DEVIATION 0.3 |
| Total testosterone | 495.0 ng/dL STANDARD_DEVIATION 198.1 | 481.3 ng/dL STANDARD_DEVIATION 230.2 | 505.3 ng/dL STANDARD_DEVIATION 206.5 | 498.1 ng/dL STANDARD_DEVIATION 160.6 |
| Waist circumference | 34.9 inch STANDARD_DEVIATION 6.3 | 36 inch STANDARD_DEVIATION 7.2 | 33.9 inch STANDARD_DEVIATION 5.2 | 34.8 inch STANDARD_DEVIATION 7 |
| Weight | 77.3 Kg STANDARD_DEVIATION 17.2 | 82.1 Kg STANDARD_DEVIATION 20.9 | 74.0 Kg STANDARD_DEVIATION 13 | 75.6 Kg STANDARD_DEVIATION 17.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 13 | 0 / 14 |
| other Total, other adverse events | 0 / 11 | 0 / 13 | 0 / 14 |
| serious Total, serious adverse events | 0 / 11 | 0 / 13 | 0 / 14 |
Outcome results
Primary
Estradiol Level in Transgender Female Patients
Degree of testosterone suppression by measuring estradiol level in transgender female patients affirming hormone therapy
Time frame: Change from baseline estradiol level at 1 and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Transdermal Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | 1 Month | 56.8 pg/mL | Standard Error 9.4 |
| Transdermal Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | baseline | 28.3 pg/mL | Standard Error 4.4 |
| Transdermal Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | 6 Months | 74.0 pg/mL | Standard Error 15.6 |
| Daily Sublingual Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | 1 Month | 52.6 pg/mL | Standard Error 9.6 |
| Daily Sublingual Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | baseline | 25.8 pg/mL | Standard Error 2.9 |
| Daily Sublingual Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | 6 Months | 95.3 pg/mL | Standard Error 10.5 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | baseline | 23.4 pg/mL | Standard Error 3.5 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | 6 Months | 79.4 pg/mL | Standard Error 11.6 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Estradiol Level in Transgender Female Patients | 1 Month | 55.2 pg/mL | Standard Error 5.2 |
Comparison: Time x treatment (month 0 and month 1)p-value: 0.951Mixed Models Analysis
p-value: 195% CI: [-29.6, 26.4]Mixed Models Analysis
p-value: 195% CI: [-35.1, 20.8]Mixed Models Analysis
Primary
Estrone Level in Transgender Female Patients
Degree of testosterone suppression by measuring estrone level in transgender female patients affirming hormone therapy
Time frame: Change from baseline estrone level at 1, and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Transdermal Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | 1 Month | 41.0 pg/ml | Standard Error 5.2 |
| Transdermal Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | baseline | 33.5 pg/ml | Standard Error 6.8 |
| Transdermal Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | 6 Months | 57.3 pg/ml | Standard Error 7.7 |
| Daily Sublingual Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | baseline | 27.7 pg/ml | Standard Error 5.7 |
| Daily Sublingual Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | 1 Month | 302 pg/ml | Standard Error 76.1 |
| Daily Sublingual Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | 6 Months | 635.7 pg/ml | Standard Error 81.3 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | baseline | 26.7 pg/ml | Standard Error 3.7 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | 6 Months | 532.9 pg/ml | Standard Error 124.6 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Estrone Level in Transgender Female Patients | 1 Month | 240.1 pg/ml | Standard Error 36.4 |
Comparison: Time x treatment (month 0 and month 1)p-value: 0.004Mixed Models Analysis
p-value: 0.00595% CI: [-487.3, -73.5]Mixed Models Analysis
p-value: 0.05495% CI: [-411.1, 2.8]Mixed Models Analysis
Primary
Total Testosterone Level in Transgender Female Patients
Degree of testosterone suppression by measuring total testosterone level in transgender female patients undergoing hormonal affirming therapy, clinical testosterone level in pg/mL
Time frame: Change from baseline total testosterone level at 1 and 6 months
Population: Baseline Measures
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Transdermal Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | 1 Month | 62.7 pg/mL | Standard Error 13.7 |
| Transdermal Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | Baseline | 498.6 pg/mL | Standard Error 46.2 |
| Transdermal Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | 6 Month | 29.4 pg/mL | Standard Error 7.4 |
| Daily Sublingual Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | 1 Month | 278.5 pg/mL | Standard Error 54.8 |
| Daily Sublingual Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | Baseline | 481.3 pg/mL | Standard Error 61.3 |
| Daily Sublingual Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | 6 Month | 108.1 pg/mL | Standard Error 46.5 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | Baseline | 505.3 pg/mL | Standard Error 53.2 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | 6 Month | 124.7 pg/mL | Standard Error 72.5 |
| Twice Daily Sublingual Estradiol Plus Spironolactone | Total Testosterone Level in Transgender Female Patients | 1 Month | 313.8 pg/mL | Standard Error 69.7 |
Comparison: Time x treatment (month 0, and 1 month)p-value: 0.005Mixed Models Analysis
p-value: 0.0295% CI: [-421.71, -28.79]Mixed Models Analysis
p-value: 0.00995% CI: [-447.1, -54.19]Mixed Models Analysis