Clinical trial NCT05010707
Conditions: Transgenderism
Keywords: Transgender female Gender affirming hormone therapy Estrogen therapy
Sponsor: Washington University School of Medicine
Start date: 2021-08-02; Completion date: 2024-01-01
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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.
Interventions: intervention 1: Transdermal patch intervention 2: Pro-thrombotic markers intervention 3: Metabolic markers intervention 4: Hormone Profile intervention 5: Daily Sublingual Tablet intervention 6: BID Sublingual Tablet intervention 7: Spironolactone
Intervention descriptions: intervention 1: 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 intervention 2: 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. intervention 3: 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. intervention 4: 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. intervention 5: 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 intervention 6: 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 intervention 7: All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose.

Protocol documents:
Prot_SAP_002.pdf: 
Study Protocol Cover page 
Title:  Effectiveness, safety, and tolerability of different estradiol dosing regimens in transgender 
females. 
NCT Number:  NCT05010707 
Date:  May 26, 2022 


Washington University in St. Louis
Version Date: May 26th, 2022
Principal Investigator: Ginger Nicol, MD
Study Title: Effectiveness, safety, and tolerability of different estradiol dosing regimens in transgender females. 
Faculty Sponsor: Thomas Baranski, MD 
•
Objectives
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 sublingual 17-beta estradiol in comparison to transdermal 17-beta estradiol for 
gender afﬁrming pharmacological therapy over the ﬁrst two-years of treatment.
This study is important because, to our knowledge, this is the ﬁrst randomized clinical trial evaluating the 
effectiveness, safety, and tolerability of estrogen in transgender female. There are no previous data comparing 
the different presentation of estrogen options in transgender women; therefore, this clinical trial will determine 
the best strategies and methods required to develop a larger randomized clinical trial. This study will also 
provide information useful to close the medical knowledge gap to provide safe and competent care to 
transgender female patients.
Aims
Aim 1. In this randomized clinical trial, we will evaluate the degree of testosterone suppression by measuring 
total testosterone level in transgender female patients undergoing hormonal afﬁrming therapy randomized to 
sublingual 17 beta estradiol or transdermal 17 beta estradiol, in conjunction with spironolactone (antiandrogen), 
for a period of 2 years.
Hypothesis 1a. Transgender females undergoing hormonal afﬁrming therapy randomized to sublingual estradiol 
with multiple daily doses will have higher degree of testosterone suppression. This hypothesis is based on the 
rationale that higher peak levels obtained with sublingual estradiol will suppress the hypothalamic-pituitary axis 
to a greater degree than the more stable levels achieved with transdermal delivery. Multiple studies (15) (18) in 
cisgender women describe the daily biological rhythm of estradiol, and a diurnal cycle of estradiol exhibiting an 
early morning peak followed by two to four recurrent cycles. However, there is no information on transgender 
patients regarding best pharmacological intervention (continuous vs pulsatile) to suppress the hypothalamic-
pituitary-gonadal axis.
Aim 2. In this randomized clinical trial, we will determine the impact on liver enzymes, metabolic proﬁle, and 
thrombogenic factors in transgender female patients undergoing hormonal afﬁrming therapy randomized to 
sublingual 17 beta estradiol or transdermal 17 beta estradiol, in conjunction with spironolactone (an 
antiandrogen), for a period of 2 years.
Hypothesis 2a. Transgender female patients on sublingual estradiol will have higher levels of estrone, which 
will lead to an increase on thrombogenic factors and changes in metabolic factors. It has been determined that 
higher estrone levels in cisgender females, has been linked with a high incidence of venous thromboembolism, 
breast cancer, and endothelial inﬂammation. An explanation for the higher thrombotic risk in postmenopausal 
women includes high production of thrombin due to high levels of estrone (12). Hypothesis 2b. Higher fat mass 
after FHT will have a negative impact on insulin sensitivity. Estradiol therapy in transgender women appears to 
be associated with an increase in fat mass and decrease in lean mass, although prospectively controlled data is 
limited (11). The increase in body fat associated with estrogen therapy raises questions about the effect on 
insulin sensitivity and cardiovascular risk. 
Purpose, Background, and Rationale
•
Background and Signiﬁcance
Transgender individuals experience discordance between their self-identiﬁed gender and biological birth sex 
(1).  Some transgender individuals experience gender dysphoria which the Diagnostic and Statistical Manual of 
Mental Disorders (DSM-5) deﬁnes as clinically signiﬁcant distress or impairment in social, occupational, or 


other key areas of functioning. Increasing numbers of adolescents seek care at gender identity centers in 
Western Countries (3). 
Studies using short self-reports of gender identity and its variants suggest that 0.17%-1.3% of adolescents and 
young adults identify as transgender (4). Even using the conservative estimate of 0.3%, the number of people 
living in the United States who identify as transgender is nearly 1 million. Health care for this population has 
historically been, and continues to be, overlooked by governmental, health care, and academic establishments 
(16). This has led to a wide range of health disparities and poor health outcomes compared with their cisgender 
counterparts (17). Given the widespread acknowledgment of the health care needs of transgender people, 
priority should be given to those actions that will ensure timely access to appropriate care. Such action includes, 
ﬁrst and foremost, coverage of transition care and a requirement to ensure safe, appropriate, and sensitive care 
in health centers (16) (17).
Transgender women seek feminizing hormone therapy (FHT) to reach feminine physical features consistent 
with their gender identity. The goal of FHT is to achieve feminine features and maintain estradiol levels within 
the normal female range while suppressing endogenous testosterone (5). Both the World Professional 
Association for Transgender Health (WPATH) and the Endocrine Society have created transgender-speciﬁc 
guidelines that serve as a framework for providers caring for gender minority patients. These guidelines are 
mostly based on clinical experience from experts in the ﬁeld. Guidelines for estrogen therapy in transgender 
women are loosely based on treatments used for postmenopausal women (6). Therefore, stronger evidence is 
needed to guide clinicians on best clinical practices for this population.
The current approach to FHT is not uniform or FDA approved 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 (9)(13). 
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 (7). 17-beta 
estradiol, which can be provided in tablet, patch, and injection, is currently the preferred formulation (8). 
Androgen blockade is usually established in all transgender females undergoing feminizing therapy and is 
achieved by either using gonadotropin blockade or antiandrogens. The latter, deﬁned as medications other than 
estradiol which are used to decrease the synthesis of or actions of androgens.  In the United States, 
spironolactone is commonly prescribed. Cyproterone acetate (CPA) is not licensed for use in the United States; 
however, CPA appears to be favored in many European countries and forms standard care as part of the 
European Network for the Investigation of Gender Incongruence (ENIGI) treatment protocol (10). 
•
Innovation
Transgender female patients suffer from poor health outcomes compared with their cisgender peers, mostly because 
feminizing therapy with estrogen has been based on data from postmenopausal women and expert opinion. This represents 
a critical gap in knowledge that prevents the delivery of safe and appropriate care for the transgender population. This 
proposal is innovative because the project is aimed to study the tolerability, safety, and differences in testosterone 
suppression of the most common 17-beta estradiol presentation while using the same antiandrogen (spironolactone). Any 
differences detected between the groups will be attributed to the estrogen effect based on their route of administration. 
Moreover, this randomized clinical trial will allow the collection of valuable preliminary data to determine the best 
strategies and methods required to develop a larger randomized clinical trial. This knowledge will set the stage for future 
feasible and sustainable interventions for transgender youth to improve health related outcomes.
•
Methods, Research Plan, and Design
•
Study design
This study will be a prospective 2-year randomized, open label, clinical trial, using daily dose sublingual versus 
twice daily dose sublingual versus transdermal 17-beta estradiol in transgender female patients.  Primary 
outcome is degree of testosterone suppression. Secondary outcome to measure safety and tolerability will 


include liver enzymes, thrombogenic, and metabolic factors. Patients will be evaluated every 6 months during 
the length of the study 
b. Subjects 
Inclusion criteria: Female transgender patients between the ages of 18 to 45 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: Use of GnRH agonist for the last 12 months, history of liver disease, dyslipidemia requiring 
treatment, drug use, alcohol use (>2drinks per day), cigarette smoking, history of blood clot (venous 
thromboembolism, pulmonary embolism), history of hyperkalemia, history of Addison’s disease, concomitant 
use of eplerenone.
Patients who have been referred to the Washington University Transgender Center for feminizing hormonal 
therapy and meet the inclusion criteria, will undergo consent process before initial evaluation. Methods for 
recruitment includes phone calls, emails, letters, and EPIC slicer dicer. For consent, physical or electronic 
consent form will be provided. 
 If consent is obtained, patients will be assigned to either daily sublingual vs twice daily sublingual vs 
transdermal 17-beta estradiol. Assignment will be done through block randomization.. Using the inclusion 
criteria, our center provides care to 150-200 new transgender female patients in a year for initiation of female 
hormone therapy.
We aim to enroll a total of 70 patients. This is a pilot study, which results will guide the feasibility, design, and 
implementation of a larger clinical trial. To account for 15% of potential dropout, we have planned to enroll a 
total of 80 patients.
•
Research Plan
The proposed clinical trial involves 2 research aims to be conducted over two years (Table 1). Subjects will be recruited 
from the Washington University Transgender Center. The Center is projected to see more than 1,000 patients every year, 
of which 150-200 are new transgender female patients for initiation of FHT. 
Patients who agree to participate in the study and meet inclusion criteria will undergo the evaluation described in Table 2. 
Data of interest will be collected on all patients enrolled and will be saved on a database created in Research Electronic 
Data Capture (REDCap). Information to be collected will include:
1. Demographic and anthropometric variables: Parameters will be routinely collected through chart review.
2. Laboratory testing: During each visit, we will obtain hormone levels, coagulation factors, metabolic factors, 
electrolytes level. A hematologist will review the lab results and communicate any recommended interventions 
(including stopping medication) to the participant’s treatment team.
Initial evaluation will include patient history, physical examination, and baseline labs. During the initial visit, 
patients will be started on spironolactone and 17-beta estradiol transdermal or or daily sublingual or twice daily 
sublingual based on their treatment group assignment. Our team will check hormonal levels every 4 weeks (+/- 
2 weeks) until estradiol level is within goal (see dosing guidelines) as established by standard of care. Once 
patients are started on estradiol, they will be asked to attend 6 more visits for the 2 years duration of the study as 
described in table 2. 
Dosing guidelines:
Per the current standard of treatment, all study medications are initiated at the lowest available clinical dose and titrated to 
effectiveness at the study clinician’s discretion by 6 months of study participation, using plasma total testosterone level in 
the cisgender female range (<50ng/dL) with serum estradiol level that should not excess the peak physiologic range 
100-200 pg/mL. In some cases, medication doses will be titrated at monthly study follow up visits to optimize treatment 
response.


Spironolactone:
Starting dose will be 50 mg daily
Plan to increase 50 mg monthly to standard dose of 200 mg daily
For patients randomized to transdermal (patch) estradiol:
Starting dose will be 100 mcg/24hrs
Plan to increase by 100 mcg/24hrs every month 
Max dose 400 mcg/24hrs
Goal is to achieve a serum estradiol level between 100-200 pg/mL and to suppress testosterone to 
cisgender female levels
Estradiol levels will be measured in the morning (fasting sample)
For patients randomized to daily sublingual estradiol:
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.
Estradiol levels will be measured in the morning (fasting sample).
For patients randomized to twice daily dose sublingual estradiol
Starting dose will be 1 mg twice 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
Estradiol levels will be measured in the morning (fasting sample).
Table 1. Planned Research Timeline
Task
Year 1
Year 2
Year 3
1
2
3
4
1
2
3
4
1
2
3
4
Obtain 
I R B 
approv
al
•
Databa
s
e 
creatio
n 
(REDC
ap)
•
Recruit
ment
•
•
•
Collect
ion of 
b l o o d 
sample
s
•
•
•
•
•
•
•
•
•
D a t a 
entry
•
•
•
•
•
•
•
•
•


D a t a 
cleanin
g and 
analysi
s
•
•
•
•
G r a n t 
applica
tion
•
•
•
•
F i n a l 
results 
manus
cript
•
•
•
Present
a t i o n 
prepara
tion
•
•
•
Table 2. Description of the evaluation and laboratory testing in each visit during the clinical trial
Study visit
Baseline
6 months
+/- 2 months
12 months
+/- 2 months
18 months
+/- 2 months
24 months
+/- 2 months
Anthropometric 
measurement 
•
•
•
•
•
Metabolic factors
•
•
•
•
•
Hormone levels
•
•
•
•
•
Electrolytes
•
•
•
•
•
Liver function test
•
•
•
•
•
Coagulation  
factors 
•
•
•
•
 
•
Lipid Panel
•
•
•
•
Beneﬁt/Risk assessment
i. Beneﬁts
Direct beneﬁts from this study to participants are anticipated. During the research study, their tolerability and 
side effects will be monitored closely so any changes can be detected earlier. Also, participants may feel 
gratiﬁed by contributing to the ﬁeld. Patients will have the opportunity to help us improve services and 
treatment options for them and future generations. 
ii. Risks
Potential risks with this study are no different than the risks that may occur while receiving gender afﬁrming 
therapy. This may include changes in their lipoprotein proﬁle and triglycerides level (14) and increase risk of 
venous thromboembolism, diabetes, high blood pressure, coronary heart disease, hepatotoxicity. While the 
patient is receiving gender afﬁrming therapy, the investigators will provide careful attention to laboratory 
results. 
Laboratory testing will be obtained every 3 months for the ﬁrst year, and every 6 months on the second year. 
For this purpose, placement of an intravenous (IV) access may be required.  IV access or venipuncture may be 
associated with possible minor discomfort or pain when inserted. 
•
Statistical methods and Data Analysis


Baseline characteristics and laboratory results will be reported as mean± SD, median (interquartile range), or 
percentages. Independent T-test will be used to analyze the difference between treatment groups. We may use 
Wilcoxon rank sum test in case of non-normal distribution.
g. Limitations and contingent plans 
A potential limitation to this study is the difﬁculty of recruitment since the PI is a First Year Clinical Fellow 
with a heavy clinical rotation. Our project is also supported by the director of the Washington University 
Transgender Center which will improve the recruitment of patients. Also, the co-directors of the Washington 
University Transgender Center at St Louis Children’s Hospital are supporting the project, therefore, we could 
increase our enrollment numbers by recruitment patients seen in their clinic. Another limitation is the cost of the 
entire panel of thrombogenic factors. We could address this by just testing the most valuable test (thrombin) 
which has been used in previous research to assess the thrombotic risk in postmenopausal women on hormone 
replacement therapy.
•
References
•
Unger CA. Hormone therapy for transgender patients. Transl Androl Urol. 2016;5(6):877-884. 
doi:10.21037/tau.2016.09.04
•
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 
Washington, DC: American Psychiatric Press; 2013
•
Kaltiala-Heino R, Bergman H, Työläjärvi M, Frisén L. Gender dysphoria in adolescence: current 
perspectives. Adolesc Health Med Ther. 2018;9:31-41. Published 2018 Mar 2. doi:10.2147/
AHMT.S135432
•
Connolly MD, Zervos MJ, Barone CJ 2nd, Johnson CC, Joseph CL. The Mental Health of Transgender 
Youth: Advances in Understanding. J Adolesc Health. 2016;59(5):489-495. doi:10.1016/
j.jadohealth.2016.06.012
•
Hamidi O, Davidge-Pitts CJ. Transfeminine Hormone Therapy. Endocrinol Metab Clin North Am. 
2019;48(2):341-355. doi:10.1016/j.ecl.2019.02.001
•
Unger CA. Hormone therapy for transgender patients. Transl Androl Urol. 2016;5(6):877-884. 
doi:10.21037/tau.2016.09.04
•
Asscheman H, Giltay EJ, Megens JA, de Ronde WP, van Trotsenburg MA, Gooren LJ. A long-term 
follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J 
Endocrinol. 2011;164(4):635-642. doi:10.1530/EJE-10-1038
•
Unger CA. Hormone therapy for transgender patients. Transl Androl Urol. 2016;5(6):877-884. 
doi:10.21037/tau.2016.09.04
•
Hamidi O, Davidge-Pitts CJ. Transfeminine Hormone Therapy. Endocrinol Metab Clin North Am. 
2019;48(2):341-355. doi:10.1016/j.ecl.2019.02.001
•
 Angus LM, Nolan BJ, Zajac JD, Cheung AS. A systematic review of antiandrogens and feminization in 
transgender women [published online ahead of print, 2020 Sep 14]. Clin Endocrinol (Oxf). 
2020;10.1111/cen.14329. doi:10.1111/cen.14329
•
Spanos C, Bretherton I, Zajac JD, Cheung AS. Effects of gender-afﬁrming hormone therapy on insulin 
resistance and body composition in transgender individuals: A systematic review. World J Diabetes. 
2020;11(3):66-77. doi:10.4239/wjd.v11.i3.66
•
Bagot CN, Marsh MS, Whitehead M, et al. The effect of estrone on thrombin generation may explain the 
different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb 
Haemost. 2010;8(8):1736-1744. doi:10.1111/j.1538-7836.2010.03953.x
•
Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/Gender-
Incongruent Persons: An Endocrine Society Clinical Practice Guideline [published correction appears in 
J Clin Endocrinol Metab. 2018 Feb 1;103(2):699] [published correction appears in J Clin Endocrinol 
Metab. 2018 Jul 1;103(7):2758-2759]. J Clin Endocrinol Metab. 2017;102(11):3869-3903. doi:10.1210/
jc.2017-01658
•
Bao AM, Liu RY, van Someren EJ, Hofman MA, Cao YX, Zhou JN. Diurnal rhythm of free estradiol 


during the menstrual cycle. Eur J Endocrinol. 2003;148(2):227-232. doi:10.1530/eje.0.1480227
•
Dutra E, Lee J, Torbati T, Garcia M, Merz CNB, Shufelt C. Cardiovascular implications of gender-
afﬁrming hormone treatment in the transgender population. Maturitas. 2019;129:45-49. doi:10.1016/
j.maturitas.2019.08.010
•
Neyman A, Fuqua JS, Eugster EA. Bicalutamide as an Androgen Blocker With Secondary Effect of 
Promoting Feminization in Male-to-Female Transgender Adolescents. J Adolesc Health. 
2019;64(4):544-546. doi:10.1016/j.jadohealth.2018.10.296
•
Stroumsa D. The state of transgender health care: policy, law, and medical frameworks. Am J Public 
Health. 2014;104(3):e31-e38. doi:10.2105/AJPH.2013.301789
•
Butler KG. Relationship Between the Cortisol-Estradiol Phase Difference and Affect in Women. J 
Circadian Rhythms. 2018;16:3. Published 2018 Feb 21. doi:10.5334/jcr.154

ICF_003.pdf: 
Informed Consent Cover page 
Title:  Effectiveness, safety, and tolerability of different estradiol dosing regimens in transgender 
females. 
NCT Number:  NCT05010707 
Date:  May 26, 2022 


INFORMED CONSENT DOCUMENT
Project Title: Effectiveness, safety, and tolerability of different estradiol dosing 
regimens in transgender females
Principal Investigator:
Ginger Nicol, MD.
Research Team Contact: Samuel Cortez, MD. Ofﬁce phone number: (314) 286-2339
           (314) 454-6051
This consent form describes the research study and helps you decide if you want to 
participate. It provides important information about what you will be asked to do during the 
study, about the risks and beneﬁts of the study, and about your rights and responsibilities as a 
research participant. By signing this form, you are agreeing to participate in this study.
You should read and understand the information in this document, including the 
procedures, risks, and potential beneﬁts. 
If you have questions about anything in this form, you should ask the research team for 
more information before you agree to participate.  
You may also wish to talk to your family or friends about your participation in this study.
Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study. 
WHAT IS THE PURPOSE OF THIS STUDY?
This is a research study. We invite you to participate in this research study because you are a 
transgender woman between 18-45 years of age. 
The purpose of this research study is to evaluate the effectiveness, safety, and tolerability of 
estrogen treatment options, speciﬁcally sublingual and transdermal estradiol. There are no 
previous data comparing the different presentation of estrogen options in transgender women. 
This study will provide useful information to close the medical knowledge gap to provide safe 
and competent care to transgender female patients. We will closely look for changes in the 
way your body processes sugars and fats. We will also obtain coagulation factors to evaluate 
the risk of blood clots.
17-beta estradiol is approved by the U.S. Food and Drug Administration to treat vasomotor 
symptoms and vaginal atrophy in post-menopausal women.  However, the use of 17-beta 
estradiol is considered investigational in this study. Spironolactone is approved by the U.S. 
Food and Drug Administration to treat high blood pressure or ﬂuid retention.  However, the use 
of Spironolactone is considered investigational in this study.
WHAT WILL HAPPEN DURING THIS STUDY?
Participants will be recruited at the Washington University Transgender Center. After the 
screening visit, if you are eligible to continue in the study, you will be randomly assigned to 
receive one of the three study treatments: spironolactone with transdermal 17-beta estradiol 
OR spironolactone with once a day sublingual 17-betaestradiol OR spironolactone with twice a 
day sublingual 17-beta estradiol. Random assignment means that in the study the treatment 
you receive will be determined purely by chance. You will have a 1 in 3 chance of receiving any 


one of the study treatments or 33.33% of getting assigned to one of the regimens. Once you 
are started on 17-beta estradiol, you will be asked to attend 4 more visits for the 2 years 
duration of the study as described in the table below. Also, once you are assigned to a study 
treatment, we will do monthly blood work until your hormone level are at goal, this step is 
required whether you are in the study or not.
Study visit
Baseline
6 months 
12 months
18 months
24 months
Vital signs and 
body 
measurements 
⎫
⎫
⎫
⎫
⎫
Metabolic factors
⎫
⎫
⎫
⎫
⎫
Hormone levels
⎫
⎫
⎫
⎫
⎫
Electrolytes
⎫
⎫
⎫
⎫
⎫
Liver function test
⎫
⎫
⎫
⎫
⎫
Coagulation  
factors 
⎫
⎫
⎫
⎫
⎫
Lipid Panel
⎫
⎫
⎫
During the length of this study, you will be seen every 6 months for the length of the study. 
During each visit, we will obtain your weight, height, body mass index (relationship between 
your weight and height), blood pressure, and waist circumference. We will also do blood work 
while fasting. The blood work will look into possible side effects of the medications that you are 
taking, including changes in your potassium level (electrolytes), the way your body is 
processing sugar and fats (blood sugar and cholesterol levels). Because of concerns of 
possible blood clots, we will study coagulation factors in your blood.
Will you save my research information and blood to use in future research studies?
We would like to use the data and blood we are obtaining in this study for studies going on 
right now, as well as studies that are conducted in the future. These studies may provide 
additional information that will be helpful in understanding the effect of gender afﬁrming 
therapy effects in the body which may lead to the development of investigational tests, 
treatments, drugs or devices that are not yet approved by the U.S. Food and Drug 
Administration. It is unlikely that what we learn from these studies will have a direct beneﬁt to 
you. There are no plans to provide ﬁnancial compensation to you should this occur. By 
allowing us to use your data and blood you give up any property rights you may have in the 
data and blood.
 
Your data and blood will be stored without your name or any other kind of link that would 
enable us to identify which sample(s) or data are yours. Therefore, it will be available 
indeﬁnitely for use in future research studies without your additional consent and cannot be 
removed.
HOW MANY PEOPLE WILL PARTICIPATE?
Approximately 80 people will take part in this study conducted by investigators at Washington 
University.  
HOW LONG WILL I BE IN THIS STUDY?
If you agree to take part in this study, your involvement will last for 2 years. You will have 5 


visits that will range from 30 to 45 minutes in length. 
WHAT ARE THE RISKS OF THIS STUDY?
Potential risks with this study are no different than the risks that may occur while receiving any 
form of gender afﬁrming therapy. These may include, but are not limited to, changes in the way 
your body processes fats increasing the risk of changes in their lipid proﬁle and triglycerides 
level, increased risk of blood clots, diabetes, high blood pressure, heart disease, and liver 
damage. Laboratory testing will be completed about every 3 months for the ﬁrst year and about 
every 6 months the second year.
Blood draw.
Common risks include:
•
The blood draw may cause bleeding, bruising, or pain.  
Rare risks include:
•
You could become dizzy or feel faint. 
•
Infection
Estradiol.
Common side effects include: 
•
Headache 
•
Breast tenderness 
•
Stomach/abdominal cramps, bloating 
•
Nausea and vomiting 
•
Hair loss 
•
Weight change
•
Decrease in frequency of erections
Other side effects include: 
•
High blood pressure 
•
Liver problems 
•
High blood sugar 
•
Fluid retention 
•
Enlargement of benign tumors ("ﬁbroids") of the uterus 
•
A spotty darkening of the skin, particularly on the face 
•
Skin rash
•
Reddening or irritation at the application site (transdermal patch)
Rare side effects include:
•
Breast cancer
•
Stroke
•
Heart attack
•
Blood clots
•
Dementia
•
Gallbladder disease
These are some of the warning signs of the rare side effects:
•
Breast lumps
•
Dizziness and faintness
•
Changes in speech
•
Severe headaches


•
Chest pain
•
Shortness of breath
•
Pains in your legs
•
Changes in vision
•
Vomiting
Spironolactone.
Common side effects include: 
•
Breast enlargement
•
Headache
•
Drowsiness
•
Increase in urination
•
Diarrhea
•
Nausea and vomiting
•
Skin rash
Rare side effects include:  
•
Hyperkalemia (elevated potassium level)
•
Hypotension (low blood pressure) and worsening renal (kidney) function
•
Electrolyte and metabolic abnormalities
•
Impaired neurological function/coma in patients with hepatic impairment, cirrhosis, and 
ascites
Breach of Conﬁdentiality
One risk of participating in this study is that conﬁdential information about you may be 
accidentally disclosed. We will use our best efforts to keep the information about you secure. 
Please see the section in this consent form titled “How will you keep my information 
conﬁdential?” for more information.
WHAT ARE THE BENEFITS OF THIS STUDY?
You will not beneﬁt from being in this study. 
However, We hope that, in the future, other people might beneﬁt from this study because the 
information learned from this study may help us improve services and treatment options for the 
future. 
WHAT OTHER TREATMENT OPTIONS ARE THERE?
Before you decide whether or not to be in this study, your doctor will discuss the other options 
that are available to you. Instead of being in this study, you could receive treatment with 
intramuscular estradiol or you can receive another similar treatment or therapy without being in 
the research study.
WILL IT COST ME ANYTHING TO BE IN THIS STUDY?
As part of this study, you will receive tests and procedures that are similar to what you would 


receive during routine clinical care of your transition. Your health plan/insurance company will 
be billed for some or all of these costs, and you will be responsible for any co-pays and 
deductibles that are normally required by your health plan/insurance. Not all insurance plans 
cover the costs associated with being in a study. Even if they do, you may be responsible for 
more out-of-pocket expenses, such as co-pays and deductibles, when there are more tests 
and procedures or more expensive tests and procedures involved in the study than if you were 
to receive routine clinical care outside the study.  
If you wish to know whether there are more tests and procedures or more expensive tests and 
procedures in the study, you should ask your study doctor.  
If you wish to know whether your insurance will pay, you should contact them directly, or speak 
with the study team about obtaining a ﬁnancial pre-certiﬁcation prior to enrolling in the study.
WILL I BE PAID FOR PARTICIPATING?
You will be paid for being in this research study. You will be given a $30 through debit card for 
each visit. There will be 3 paid in-person visits, for a total of $90. You will be asked to provide 
your social security number (SSN).. We will provide you with information about any fees or 
restrictions on the use of the debit card.
WHO IS FUNDING THIS STUDY?
The National Institutes of Health (NIH) is funding this research study.  This means that 
Washington University is receiving payments from the NIH to support the activities that are 
required to conduct the study.  No one on the research team will receive a direct payment or 
increase in salary from the NIH for conducting this study.
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY?
Washington University investigators and staff will try to reduce, control, and treat any 
complications from this research. If you feel you are injured because of the study, please 
contact the investigator at : (314) 286-2339 OR (314) 454-6051, and/or the Human Research 
Protection Ofﬁce at 1-(800)-438-0445. 
Decisions about whether payment for medical treatment for injuries relating to your 
participation in research will be made by Washington University. If you need to seek medical 
care for a research-related injury, please notify the investigator as soon as possible.
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL?
Other people such as those indicated below may become aware of your participation in this 
study and may inspect and copy records pertaining to this research. Some of these records 
could contain information that personally identiﬁes you. We will keep your participation in this 
research study conﬁdential to the extent permitted by law.  
•
Government representatives (including the Ofﬁce for Human Research Protections) to 
complete federal or state responsibilities.
•
The U.S. Food and Drug Administration
•
The National Institutes of Health


•
Hospital or University representatives to complete Hospital or University responsibilities.
•
Information about your participation in this study may be documented in your health 
care records and will be available to anyone with access to your health care record, 
including your health insurance company. This information may also be released as part 
of a release of information request.
•
The last four digits of your social security number may be used in hospital or University 
systems to track billing information for research procedures.
•
Washington University’s Institutional Review Board (a committee that oversees the 
conduct of research involving human participants) and the Human Research Protection 
Ofﬁce. The Institutional Review Board has reviewed and approved this study. 
•
Any report or article that we write will not include information that can directly identify 
you.  The journals that publish these reports or articles require that we share your 
information that was collected for this study with others to make sure the results of this 
study are correct and help develop new ideas for research. Your information will be 
shared in a way that cannot directly identify you.
To help protect your conﬁdentiality, we will:
•
Consent will be obtained in a private setting
•
Obtain only the minimum necessary private information
•
Procedures (like blood draw) will be conducted in a private setting
•
All information will be secured in a password-protected secured environment (REDCap 
database)
•
Access to the information collected will be limited to the research team members only
•
Each participant will be provided a unique code/number to collect their information 
(coded information)
•
Information collected from participants will be saved under the assigned code/number
•
Blood sample will be collected under the code/number assigned to each participant, this 
way we will assure the specimens are de-identiﬁed.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
To further protect your privacy, this research is covered by a Certiﬁcate of Conﬁdentiality from 
the federal government. This means that the researchers can refuse to disclose information 
that may identify you in any legal or court proceeding or to anyone who is not connected with 
the research except if: 
•
there is a law that requires disclosure, such as to report child abuse and neglect, or 
harm to self or others; 
•
you give permission to disclose your information, including as described in this consent 
form; or
•
it is used for other scientiﬁc research allowed by federal law.
This Certiﬁcate may not be effective for information held in foreign countries.


You have the right to share your information or involvement in this study with anyone at any 
time. You may also give the research team permission to disclose your information to a third 
party or any other person not connected with the research. 
Are there additional protections for my health information?
Protected Health Information (PHI) is health information that identiﬁes you. PHI is protected by 
federal law under HIPAA (the Health Insurance Portability and Accountability Act). To take part 
in this research, you must give the research team permission to use and disclose (share) your 
PHI for the study as explained in this consent form. The research team will follow state and 
federal laws and may share your health information with the agencies and people listed under 
the previous section titled, “How will you keep my information conﬁdential?”
Once your health information is shared with someone outside of the research team, it may no 
longer be protected by HIPAA.  
The research team will only use and share your information as talked about in this form or as 
permitted or required by law. When possible, the research team will make sure information 
cannot be linked to you (de-identiﬁed). Once information is de-identiﬁed, it may be used and 
shared for other purposes not discussed in this consent form. If you have questions or 
concerns about your privacy and the use of your PHI, please contact the University’s Privacy 
Ofﬁcer at 866-747-4975. 
Although you will not be allowed to see the study information, you may be given access to your 
health care records by contacting your health care provider. 
If you decide not to sign this form, it will not affect:
your treatment or the care given by your health provider.
your insurance payment or enrollment in any health plans.  
any beneﬁts to which you are entitled.
However, it will not be possible for you to take part in the study.
If you sign this form:
•
You authorize the use of your PHI for this research.
•
This authorization does not expire.
You may later change your mind and not let the research team use or share your 
information (you may revoke your authorization). 
•
To revoke your authorization, complete the withdrawal letter, found in the 
Participant section of the Human Research Protection Ofﬁce website at https://
hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter.   
o
If you revoke your authorization:
♣The research team may only use and share information already 
collected for the study.
♣Your information may still be used and shared as necessary to 


maintain the integrity of the research, for example, to account for a 
participant’s withdrawal from the research study or for safety reasons.
♣You will not be allowed to continue to participate in the study.
Can we contact you by email and text message?
We would like to contact you by email and text message for the purposes listed below.  Some 
of these messages may contain health information that identiﬁes you.
•
Educational material regarding your condition and medications that you are 
taking
•
Remind you about future/upcoming appointment
•
Coordinate future appointments
•
Discuss blood work and medication updates
•
Ask about prescription reﬁlls
Only the research team will have access to your email and text communications. We will only 
communicate in this method to send you the information listed above. If you have any 
questions, wish us to stop sending these messages or need to contact us for an urgent or 
emergent situation, please contact the research team member identiﬁed at the top of this 
document.
You should be aware that there are risks associated with sending your health information via 
email and text.  
•
Text messaging is not a secure communication method.
•
There is always a risk that the message could be intercepted or sent to the wrong 
email address and/or phone number. To avoid this, we will send a test message to 
ensure we have the correct email address and/or phone number.
•
For email, when using any computer you should be careful to protect your 
username and password. Make sure you log-out before getting up from the 
computer.  
•
If you share a home computer or cell phone with other family members, and do 
not want them to know you are participating in this study make sure you provide an 
email address that only you can access. 
•
Your employer will have access to any messages sent or received on any 
electronic devices used for work or through a work server.
•
If you lose your phone, others may be able to access the messages that we 
send.
 
Do you agree to allow us to send your health information via email?  
_____ Yes 
_____ No
Initials
Initials
Do you agree to allow us to send your health information via text?  
_____ Yes 
_____ No


Initials
Initials
IS BEING IN THIS STUDY VOLUNTARY?
Taking part in this research study is completely voluntary.  You may choose not to take part at 
all.  If you decide to be in this study, you may stop participating at any time. Any data that was 
collected as part of your participation in the study will remain as part of the study records and 
cannot be removed.  
If you decide not to be in this study, or if you stop participating at any time, you will not be 
penalized or lose any beneﬁts for which you otherwise qualify. 
 
What if I decide to withdraw from the study?
You may withdraw by telling the study team you are no longer interested in participating in the 
study or you may send in a withdrawal letter. A sample withdrawal letter can be found at https://
hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study.
Will I receive new information about the study while participating?
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we will promptly provide you with that information.
WHAT IF I HAVE QUESTIONS?
We encourage you to ask questions. If you have any questions about the research study itself, 
please contact Ginger Nicol, MD at (314) 286-2339 OR (314) 454-6051 
If you have questions, concerns, or complaints about your rights as a research participant, 
please contact the Human Research Protection Ofﬁce 1-(800)-438-0445, or email 
hrpo@wustl.edu.   General information about being a research participant can be found on the 
Human Research Protection Ofﬁce web site, http://hrpo.wustl.edu.  To offer input about your 
experiences as a research participant or to speak to someone other than the research staff, 
call the Human Research Protection Ofﬁce at the number above.
This consent form is not a contract. It is a written explanation of what will happen during the 
study if you decide to participate. You are not waiving any legal rights by agreeing to 
participate in this study. As a participant you have rights and responsibilities as described in 
this document and including:
• To be given enough time before signing below to weigh the risks and potential beneﬁts 
and decide if you want to participate without any pressure from the research team or 
others.
• To understand all of the information included in the document, have your questions 
answered, and receive an explanation of anything you do not understand.
• To follow the procedures described in this document and the instructions of the research 
team to the best of your ability unless you choose to stop your participation in the 
research study.
• To give the research team accurate and complete information.
• To tell the research team promptly about any problems you have related to your 


participation, or if you are unable to continue and wish to stop participating in the 
research study.
Your signature indicates that this research study has been explained to you, that your 
questions have been answered, and that you agree to take part in this study.  You will receive 
a signed and dated copy of this form.
Do not sign this form if today’s date is after EXPIRATION DATE: 04/12/23.
__________________________________________ _______________________________
(Signature of Participant)
(Date)
____________________________________________
(Participant's name – printed)
Statement of Person Who Obtained Consent
The information in this document has been discussed with the participant or, where 
appropriate, with the participant’s legally authorized representative. The participant has 
indicated that they understand the risks, beneﬁts, and procedures involved with participation in 
this research study.
__________________________________________ _______________________________
(Signature of Person who Obtained Consent)
(Date)
___________________________________________
(Name of Person who Obtained Consent - printed)