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CompletedNCT05010707TREATUpdated Nov 26, 2024Results posted

Transgender Estradiol Affirming Therapy

A Phase 2 interventional study of Transdermal patch and Pro-thrombotic markers in Transgenderism, sponsored by Washington University School of Medicine. Completed at 1 site in United States. Open to male participants aged 18 Years to 30 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-11-26.

Sponsored by Washington University School of Medicine · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
39
Allocation
Randomized
Ages
18 Years to 30 Years
Sex
Male
01

Study 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.

Read the 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.

02

Conditions studied

  • Transgenderism

Keywords

  • Transgender female
  • Gender affirming hormone therapy
  • Estrogen therapy
03

In context

Lead sponsor

Washington University School of Medicine is the lead sponsor of 1,765 studies on the registry; 271 are open to participants now.

Of its 324 completed or terminated interventional studies of FDA-regulated products, 212 (65%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 30 Years
Sexes eligible
Male
Accepts 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

Exclusion Criteria:

  • GnRH agonist for the last 12 months
  • History of liver disease
  • Dyslipidemia requiring treatment
  • Cigarette smoking
  • Body mass index >30 kg/m2
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
39 participants (actual)

Study arms

  • Active comparator
    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.

    Drug: Transdermal patch · Diagnostic Test: Pro-thrombotic markers · Diagnostic Test: Metabolic markers · Diagnostic Test: Hormone Profile · Drug: Spironolactone

  • Active comparator
    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.

    Diagnostic Test: Pro-thrombotic markers · Diagnostic Test: Metabolic markers · Diagnostic Test: Hormone Profile · Drug: Daily Sublingual Tablet · Drug: Spironolactone

  • Active comparator
    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.

    Diagnostic Test: Pro-thrombotic markers · Diagnostic Test: Metabolic markers · Diagnostic Test: Hormone Profile · Drug: BID Sublingual Tablet · Drug: Spironolactone

Interventions

  • DrugTransdermal 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

    Also known as: Daily

  • 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

    Also known as: Once daily dosing

  • 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

    Also known as: Twice daily dosing

  • DrugSpironolactone

    All patients will also receive spironolactone. Spironolactone will be started at 50 mg daily and will increase to standard dose.

    Also known as: Daily

06

What researchers measure

Primary outcomes

  1. 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

  2. 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

  3. 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

07

Results

Posted Nov 26, 2024

Participant flow

Participant flow — Overall Study
MilestoneTransdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus Spironolactone
Started121314
Completed111214
Not completed110

Outcome measures

PrimaryTotal 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
Reported as:
Mean · pg/mL
Total Testosterone Level in Transgender Female Patients
pg/mLTransdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus Spironolactone
Baseline498.6 ± 46.2481.3 ± 61.3505.3 ± 53.2
1 Month62.7 ± 13.7278.5 ± 54.8313.8 ± 69.7
6 Month29.4 ± 7.4108.1 ± 46.5124.7 ± 72.5
Statistical analysis
  • Transdermal Estradiol Plus Spironolactone vs Daily Sublingual Estradiol Plus Spironolactone vs Twice Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 0.005
  • Transdermal Estradiol Plus Spironolactone vs Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 0.02 · Mean difference (final values): -225.3 · 95% CI -421.71 to -28.79
  • Transdermal Estradiol Plus Spironolactone vs Twice Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 0.009 · Mean difference (final values): -250.6 · 95% CI -447.10 to -54.19
PrimaryEstradiol 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
Reported as:
Mean · pg/mL
Estradiol Level in Transgender Female Patients
pg/mLTransdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus Spironolactone
baseline28.3 ± 4.425.8 ± 2.923.4 ± 3.5
1 Month56.8 ± 9.452.6 ± 9.655.2 ± 5.2
6 Months74.0 ± 15.695.3 ± 10.579.4 ± 11.6
Statistical analysis
  • Transdermal Estradiol Plus Spironolactone vs Daily Sublingual Estradiol Plus Spironolactone vs Twice Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 0.951
  • Transdermal Estradiol Plus Spironolactone vs Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 1 · Mean difference (final values): -1.6 · 95% CI -29.6 to 26.4The mean difference is computed using the model based estimates rather than from the raw data.
  • Transdermal Estradiol Plus Spironolactone vs Twice Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 1 · Mean difference (final values): -7.1 · 95% CI -35.1 to 20.8The mean difference is computed using the model based estimates rather than from the raw data.
PrimaryEstrone 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
Reported as:
Mean · pg/ml
Estrone Level in Transgender Female Patients
pg/mlTransdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus Spironolactone
baseline33.5 ± 6.827.7 ± 5.726.7 ± 3.7
1 Month41.0 ± 5.2302 ± 76.1240.1 ± 36.4
6 Months57.3 ± 7.7635.7 ± 81.3532.9 ± 124.6
Statistical analysis
  • Transdermal Estradiol Plus Spironolactone vs Daily Sublingual Estradiol Plus Spironolactone vs Twice Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 0.004
  • Transdermal Estradiol Plus Spironolactone vs Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 0.005 · Mean difference (final values): -280.4 · 95% CI -487.3 to -73.5
  • Transdermal Estradiol Plus Spironolactone vs Twice Daily Sublingual Estradiol Plus Spironolactone · Mixed Models Analysis · p = 0.054 · Mean difference (final values): -204.1 · 95% CI -411.1 to 2.8

Adverse events

Collected over The time frame is until the study's completion, an average of 12 months.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Transdermal Estradiol Plus Spironolactone0/11 (0%)0/11 (0%)0/11 (0%)
Daily Sublingual Estradiol Plus Spironolactone0/13 (0%)0/13 (0%)0/13 (0%)
Twice Daily Sublingual Estradiol Plus Spironolactone0/14 (0%)0/14 (0%)0/14 (0%)

Baseline characteristics

A total number of 39 participants had the demographic information.

Age, Categorical
Age, Categorical(Participants)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
<=18 years0000
Between 18 and 65 years12131439
>=65 years0000
Age, Continuous
Age, Continuous(years)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
Median25.3 (18.2 to 42.6)25.0 (19.0 to 37.2)21.5 (18.9 to 33.5)25.3 (18.2 to 42.6)
Sex: Female, Male
Sex: Female, Male(Participants)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
Female12131439
Male0000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
American Indian or Alaska Native0000
Asian2002
Native Hawaiian or Other Pacific Islander0000
Black or African American0123
White9121132
More than one race0000
Unknown or Not Reported1012
Region of Enrollment
Region of Enrollment(Participants)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
United States12131439
Weight
Weight(Kg)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
Mean75.6 ± 17.282.1 ± 20.974.0 ± 13.077.3 ± 17.2
BMI
BMI(kg/m^2)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
Mean25.2 ± 5.926.2 ± 7.223.9 ± 5.025.1 ± 6.0
Systolic blood pressure
Systolic blood pressure(mmHg)Transdermal Estradiol Plus SpironolactoneDaily Sublingual Estradiol Plus SpironolactoneTwice Daily Sublingual Estradiol Plus SpironolactoneTotal
Mean132.8 ± 12.6140.8 ± 21.7128.3 ± 16.9134.0 ± 18.0

20 further baseline measures are reported on the registry.

08

Study locations

1 site
  • Washington University Transgender Center
    Saint Louis, Missouri 63112, United States
09

References and documents

Publications

  • Unger CA. Hormone therapy for transgender patients. Transl Androl Urol. 2016 Dec;5(6):877-884. doi: 10.21037/tau.2016.09.04. PubMed 28078219 ↗
  • Kaltiala-Heino R, Bergman H, Tyolajarvi M, Frisen L. Gender dysphoria in adolescence: current perspectives. Adolesc Health Med Ther. 2018 Mar 2;9:31-41. doi: 10.2147/AHMT.S135432. eCollection 2018. PubMed 29535563 ↗
  • Connolly MD, Zervos MJ, Barone CJ 2nd, Johnson CC, Joseph CL. The Mental Health of Transgender Youth: Advances in Understanding. J Adolesc Health. 2016 Nov;59(5):489-495. doi: 10.1016/j.jadohealth.2016.06.012. Epub 2016 Aug 17. PubMed 27544457 ↗
  • Hamidi O, Davidge-Pitts CJ. Transfeminine Hormone Therapy. Endocrinol Metab Clin North Am. 2019 Jun;48(2):341-355. doi: 10.1016/j.ecl.2019.02.001. Epub 2019 Mar 23. PubMed 31027544 ↗
  • 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 Apr;164(4):635-42. doi: 10.1530/EJE-10-1038. Epub 2011 Jan 25. PubMed 21266549 ↗
  • 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. PubMed 32926454 ↗
  • 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 Mar 15;11(3):66-77. doi: 10.4239/wjd.v11.i3.66. PubMed 32180895 ↗
  • Bagot CN, Marsh MS, Whitehead M, Sherwood R, Roberts L, Patel RK, Arya R. The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb Haemost. 2010 Aug;8(8):1736-44. doi: 10.1111/j.1538-7836.2010.03953.x. Epub 2010 Jun 14. PubMed 20553380 ↗
  • 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. PubMed 28945902 ↗
  • 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 Feb;148(2):227-32. doi: 10.1530/eje.0.1480227. PubMed 12590642 ↗

Study documents

  • Protocol and statistical analysis plan · May 26, 2022
  • Informed consent form · May 26, 2022

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Nov 26, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT05010707
Lead sponsor
Washington University School of Medicine
Responsible party
Ginger E Nicol (Associate Professor of Child & Adolescent Psychiatry, Washington University School of Medicine) — Principal investigator
First posted
Aug 18, 2021
Start date
Aug 2, 2021
Primary completion
Aug 1, 2023
Completion
Jan 1, 2024
Results posted
Nov 26, 2024
Last update
Nov 26, 2024

Study contacts

Ginger Nicol, MD
principal investigator · Washington University School of Medicine

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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