Progesterone in Gender Affirming Hormone Therapy Study

Phase 2

Recruiting

• Conditions: Transgender Women
• Interventions: Drug: Placebo; Drug: Progesterone

• Registration Number: NCT06807580
• Lead Sponsor: Emory University

Brief Summary

This study aims to study the effects of Oral Progesterone in Transgender Women. The primary goal is to study the effect of progesterone on psychological distress and secondarily on sleep quality, breast size, quality of life and gender congruence and cardiovascular risk.

Detailed Description

The transgender population in the U.S. has grown significantly, highlighting a lack of comprehensive research on the safety and efficacy of gender-affirming hormone therapy (GAHT). For transgender females, GAHT typically includes estrogen and an anti-androgen. Recently, there has been growing interest in adding progesterone, based on anecdotal reports of improved breast development and quality of life. However, progesterone's role in transgender women remains unclear.

Studies have linked progesterone (mainly cyproterone acetate) to increased risks of meningiomas, elevated prolactin levels, decreased testosterone, reduced HDL levels, and higher venous thromboembolism (VTE) risk. Cyproterone acetate, often studied in these contexts, is not FDA-approved in the U.S. due to hepatotoxicity, and its use in GAHT is rare. Limited research exists on micronized progesterone, the form most commonly prescribed.

A recent study on low-dose micronized progesterone found no significant effects on sleep quality, psychological distress, or breast development. To address research gaps, a new study aims to evaluate higher-dose micronized progesterone's impact on cardiovascular risk, sleep quality, breast development, and psychological distress over a longer period. The hypothesis suggests neutral effects on breast development, sleep, and quality of life, with potential negative to neutral cardiovascular effects.

Given the lack of recommendations for or against progesterone in GAHT, further research is critically needed.

Study Timeline

• Study First Submitted: 2025-01-29
• Study First Submitted QC: 2025-01-29
• Study First Posted: 2025-02-04
• Status Verified: 2025-05
• Study Start: 2025-05-12
• Last Update Submitted: 2025-05-13
• Last Update Posted: 2025-05-16
• Primary Completion: 2027-02
• Study Completion: 2027-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 40

Inclusion Criteria

• Participants will be transgender women, who have been on gender-affirming hormone therapy for at least 6 months before the start of the study.

Exclusion Criteria

• Peanut allergy
• Liver disease (liver enzyme elevations and/or evidence of acute or chronic hepatitis). In our lab, the upper limit of normal for aspartate aminotransferase (AST) is 39, and the upper limit of normal for alanine aminotransferase (ALT) is 52.
• Stage 4/5 chronic kidney disease
• Congestive heart failure
• Medical disease or medication use associated with gynecomastia (i.e tumor, hyperthyroidism, chronic kidney disease, cirrhosis, ACE inhibitors, statins, haloperidol, tricyclic antidepressants, atypical antipsychotics)
• Pre-existing cardiovascular disease
• Prior or current history of thromboembolism, known clotting disorders, current or recent anti-thrombotic therapy for venous thromboembolism.
• History of breast cancer
• Prior progesterone use
• Uncontrolled depression and/or suicidal ideation
• Current hypothyroidism (even if controlled with treatment) Progesterone in Gender Affirming Hormone Therapy 9 Version #4, 10/30/24
• Current or recent (in the past 6 months) cannabis use
• Previously identified BRCA 1 or 2 gene mutation or other familial breast cancer.
• Abnormal mammogram (if indicated - for patients above the age of 50 and on estrogen for 5 or more years OR positive family history of breast cancer) with results of BIRADS 3 or higher. Subjects with a BIRADS 0 mammogram must have undergone additional imaging demonstrating BIRADS 1 or 2 prior to enrollment.
• Have had or are planning to undergo breast enhancement or gender affirming top surgery in the next 6 months
• Uncontrolled hypertension, defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mmHg.
• Triglycerides ≥ 500 mg/dL.
• In our lab, the upper limit of normal for aspartate aminotransferase (AST) is 39, and the upper limit of normal for alanine aminotransferase (ALT) is 52.
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2.
• Estradiol levels outside the stable range (100-200 pg/mL)
• Heavy smoking, defined as 25+ cigarettes per day
• Non-English speaking or those with limited English proficiency

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A	Placebo	Group A will serve as our control group with participants on their existing gender-affirming therapy in addition to a placebo pill. Laboratory assessments including estradiol, lipid profile, and Complete metabolic profile (CMP) will be performed at screening.
Group B	Progesterone	Group B will serve as our intervention group with participants on their existing gender-affirming therapy in combination with 200 mg oral micronized progesterone at bedtime. Laboratory assessments including estradiol, lipid profile, and Complete metabolic profile (CMP) will be performed at screening.

Primary Outcome Measures

Name	Time	Method
Psychological Distress	Baseline, Month 6	Kessler Psychological Distress Scale (K10) scale will be used to measure distress.; This is a 10-item questionnaire intended to yield a global measure of distress based on questions about anxiety and depressive symptoms that a person has experienced in the most recent 4 week period.; The numbers attached to the patients 10 responses are added up and the total score is the score on the Kessler Psychological Distress Scale (K10). Scores will range from 10 to 50. People seen in primary care who: * score under 20 are likely to be well; * score 20-24 are likely to have a mild mental disorder; * score 25-29 are likely to have moderate mental disorder; * score 30 and over are likely to have a severe mental disorder

Secondary Outcome Measures

Name	Time	Method
Effect of progesterone on breast development	Baseline, Month 6	Breast size will be measured using hemi-circumference. Hemi circumference will be measured as the medial breast infliction point, the most medial point of the breast across the nipple level to the lateral breast inflection point.
Effect of progesterone on sleep quality	Baseline, Month 6	Sleep quality will be measured by having participants from both Group A and B take the 19 item Pittsburgh sleep index. The Pittsburgh Sleep Quality Index (PSQI) is a 19-item questionnaire that assesses sleep quality and disturbances over the past month.; Each item is scored on a scale of 0-3, with 3 being the worst. The global score ranges from 0-21, with higher scores indicating worse sleep quality.
Effect of progesterone on gender congruence	Baseline, Month 6	The gender Congruence and Life Satisfaction Scale (GCLS) will be used. It is a 38-item scale with each item scored on a 5-point scale.; Items are scored on a 5-point scale (always = 1; never = 5). A higher score indicates a more positive outcome (higher gender congruence, better gender-related mental well-being, and better general life satisfaction).
Effect of progesterone on cardiovascular risk	Baseline, Month 6	Change in lipid profile from baseline.

Trial Locations

Locations (1)

Emory Transgender Clinic; 🇺🇸 Atlanta, Georgia, United States