Cardiometabolic Health in Transgender Males

September 29, 2025 updated by: Susanne Cabrera, Medical College of Wisconsin

Defining the Cardiometabolic Profile of Transgender Boys and Men on Testosterone Therapy

Transgender individuals are those with a gender identity opposite the sex they were assigned at birth. Approximately 1% of the population is transgender, equating to ~60,000 transgender Wisconsinites. A transgender boy or man is someone with a 46,XX karyotype and typical female genitalia but a male gender identity and desire for more male-typical gender expression. Gender-affirming testosterone (hormonal) treatment (GAHT) is the cornerstone of masculinizing therapy for transgender men and boys, resulting in estrogen (E2) suppression and circulating testosterone (T) levels equivalent to cisgender males. Historically, GAHT was initiated after an E2-driven puberty, but the last decade has seen an explosion of referrals for GAHT in transboys, many of whom are exposed to only low E2 levels before puberty is halted with blocker therapy. Knowledge of risks incurred by GAHT rely on low-quality studies, precluding conclusive assessment of GAHT's long-term impact on cardiometabolic outcomes. Data on transboys receiving GAHT before completion of E2-driven puberty are sparser and no studies have addressed mechanisms by which GAHT may affect vascular physiology. The investigators aim to determine the cardiometabolic impact of GAHT in transboys/men and to determine if any differences identified are mechanistically dependent on the timing of GAHT relative to puberty.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Detailed Description

Gender-affirming testosterone (hormonal) treatment (GAHT) is the cornerstone of masculinizing therapy for transgender men, resulting in circulating testosterone (T) levels equivalent to cismen and estrogen (E2) suppression. Historically, GAHT was initiated after an E2-driven puberty, but the last decade has seen an explosion of referrals for GAHT in transboys, many of whom are exposed to only low E2 levels before puberty is halted with blocker therapy. Knowledge of risks incurred by GAHT rely on low quality studies, precluding conclusive assessment of GAHT's long-term impact on cardiometabolic outcomes. Data on transboys receiving GAHT before completion of E2-driven puberty are sparser and no studies have addressed mechanisms by which GAHT may affect vascular physiology. The investigators aim to determine the cardiometabolic impact of GAHT in transboys/men and to determine if any differences identified are mechanistically dependent on the timing of GAHT relative to puberty. The vaso-protective benefits of E2 are well-described; higher circulating E2 begins in female puberty, stimulating a long-term increase in the vascular expression of the E2 receptor's alpha isoform (ERα). ERα activation directly stimulates nitric oxide (NO) production from endothelium-derived NO synthase and is critical to maintaining a healthy vascular endothelium. Pre-menopausal women have an increased capacity to produce endothelial NO due to higher E2 levels and vascular ERα expression, resulting in lower cardiovascular disease risk vs age-matched cismen. These data suggest a novel paradigm for the impact of GAHT on vascular health in transmen that differs depending on when GAHT is initiated relative to puberty. The investigators hypothesize that, in transmen who have completed E2-driven puberty, GAHT will induce a regression of vascular endothelial function towards that of cismen by suppressing circulating E2 and ERα expression and that similar regression will not be seen in transboys initiating GAHT prior to pubertal progression. The investigators propose, to our knowledge, a first-of-its-kind longitudinal study of the cardiometabolic impact of 1-year of GAHT in 40 transboys and transmen as compared to cisgender controls with endogenous sex hormones. The impact of GAHT initiation and continuation in transboys/men on in vivo and ex vivo vascular endothelial function, estrogen-stimulated endothelial vasorelaxation, and expression of vascular ERα expression will be determined by measuring changes in conduit vessel endothelium-dependent vasodilation and vascular E2 receptor expression and responsiveness in transboys on puberty blockers and in transmen. The investigators will also determine whether GAHT suppresses the human arteriolar vascular expression of ERα receptors and reduces E2-stimulated endothelial vasorelaxation in transboys/men relative to ciswomen. Secondarily, The investigators will characterize the metabolic, body composition and inflammatory impact of GAHT. This study will provide a novel mechanistic framework for the cardiometabolic impact of GAHT and make available critical information for care providers and patients on how GAHT may affect their cardiovascular risk.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
90

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

12 years to 30 years (Child, Adult)

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

EXCLUSION CRITERIA FOR TRANSGENDER AND CISGENDER INDIVIDUALS

  1. Any disease affecting glucose, sex steroid, or fat metabolism such as diabetes, polycystic ovary syndrome, or clinical suspicion of insulin resistance)
  2. Any medication use that may affect glucose, sex steroid, or fat metabolism such as metformin or glucocorticoids
  3. Known cardiovascular disease such as hypertension or atherosclerosis
  4. Raynaud's phenomenon or other vascular disease
  5. BMI > 40 kg/m2 for those aged ≥ 18 years or > 95% percentile for age- and sex-assigned at birth in those aged < 18 years
  6. Pregnancy or lactation
  7. Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.

Description

Inclusion Criteria:

  • INCLUSION CRITERIA FOR TRANSGENDER BOYS AND TRANSGENDER MEN

    1. Sex assigned female at birth and a male gender identity (i.e., transgender male)
    2. Aged 12-30 years
    3. Have a care provider in the Children's Wisconsin Gender Health Clinic or Froedtert Hospital Inclusion Clinic who has determined the individual meets clinical criteria to start testosterone therapy and plans to initiate this therapy
    4. Naïve to testosterone or other masculinizing medical therapy
    5. Cisgender girls/women and transgender boys/men of child-bearing potential (defined as having achieved menarche (first menses), excluding those who have had a hysterectomy or are on GnRH agonist therapy (puberty blockers)) must be willing to use effective birth control (which may include abstinence)) from screening visit until final study visit
    6. Willing and able to give informed consent or have parent or legal guardian provide informed consent if the subject is < 18 years of age

INCLUSION CRITERIA FOR CISGENDER INDIVIDUALS

  1. Gender identity concordant with sex assigned at birth (i.e., cisgender)
  2. Aged 12-30 years
  3. Not related to a transgender participant enrolled in the study
  4. Naïve to any sex hormone or pubertal blocker therapy or, specific to cisgender girls/women only, must be ≥ 1 year from use of oral contraceptive or other contraceptive technique (intrauterine device, medroxyprogesterone injections)
  5. Willing and able to give informed consent or have parent or legal guardian provide informed consent if the subject is < 18 years of age

INCLUSION CRITERIA FOR OPTIONAL NITROGLYCERIN ENDOTHELIUM-INDEPENDENT VASCULAR FUNCTION STUDY

  1. Aged ≥ 18 years
  2. No history of migraine headaches
  3. Systolic blood pressure ≥ 110 mm Hg
  4. No prior past adverse reaction to nitroglycerin
  5. Has not used a PDE5 inhibitor (i.e., sildenafil, tadalafil, vardenafil) in the past 7 days

Exclusion Criteria:

-

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Transgender Males
Individuals assigned female gender at birth but considering gender-affirming testosterone therapy. May self-identify as transgender or nonbinary etc.
Cisgender Controls
Individuals assigned male or female at birth. May identify as cisgender or nonbinary etc. These individuals should not be undergoing or considering any form of hormone therapy.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in vascular endothelial function after one year of gender-affirming testosterone therapy as measured by brachial artery ultrasound flow-mediated dilation
Time Frame: 1 year from baseline study visit
Investigators will examine the effects of gender-affirming testosterone therapy on in vivo endothelial function by brachial artery ultrasound flow-mediated dilation across study visits.
1 year from baseline study visit
Change in vascular endothelial function after one year of gender-affirming testosterone therapy as measured by by blood pressure.
Time Frame: 1 year from baseline study visit
Investigators will examine the effects of gender-affirming testosterone therapy on in vivo endothelial function by blood pressure.
1 year from baseline study visit
Change in vascular endothelial function after one year of gender-affirming testosterone therapy as measured by circulating markers of endothelial activation as measured by plasma analysis
Time Frame: 1 year from baseline study visit
Investigators will examine the effects of gender-affirming testosterone therapy on in vivo endothelial function by circulating markers of endothelial activation as measured by plasma analysis.
1 year from baseline study visit

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in body composition after one year of gender-affirming testosterone therapy as measured by BMI
Time Frame: 1 year from baseline study visit
Investigators will examine the effect of gender-affirming testosterone therapy on body composition as quantified by body mass index (BMI).
1 year from baseline study visit
Change in body composition after one year of gender-affirming testosterone therapy as measured by DXA scans.
Time Frame: 1 year from baseline study visit
Investigators will examine the effect of gender-affirming testosterone therapy on body composition as quantified by total body dual-energy X-ray absorptiometry (DXA) scan which provides information about the amount and distribution of fat and muscle in the body.
1 year from baseline study visit
Change in body composition after one year of gender-affirming testosterone therapy as measured by the ratio of waist-to-hip circumference.
Time Frame: 1 year from baseline study visit
Investigators will examine the effect of gender-affirming testosterone therapy on body composition as quantified by the ratio of waist-to-hip circumference which provides information about the amount and distribution of fat and muscle in the body.
1 year from baseline study visit
Change in lipid profile after one year of gender-affirming testosterone therapy
Time Frame: 1 year from baseline study visit
Investigators will measure the effect of gender-affirming testosterone therapy on the various components of a fasting lipid profile (triglyceride level, HDL, LDL, and total cholesterol).
1 year from baseline study visit
Change in systemic inflammation after one year of gender-affirming testosterone therapy
Time Frame: 1 year from baseline study visit
Investigators will examine the effect of gender-affirming testosterone therapy on circulating levels of inflammatory cytokines as measured by plasma analysis.
1 year from baseline study visit
Change in glucose metabolism after one year of gender-affirming testosterone therapy as measured by fasting insulin level in the blood.
Time Frame: 1 year from baseline study visit
Investigators will examine the effect of gender-affirming testosterone therapy on fasting insulin.
1 year from baseline study visit
Change in glucose metabolism after one year of gender-affirming testosterone therapy as measured by fasting blood glucose level.
Time Frame: 1 year from baseline study visit
Investigators will examine the effect of gender-affirming testosterone therapy on fasting glucose.
1 year from baseline study visit
Change in glucose metabolism after one year of gender-affirming testosterone therapy as measured by HbA1c
Time Frame: 1 year from baseline study visit
Investigators will examine the effect of gender-affirming testosterone therapy on HbA1c levels.
1 year from baseline study visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Medical College of Wisconsin

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Advancing a Healthier Wisconsin

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 30, 2021

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 31, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 25, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 15, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 27, 2021

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 3, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 29, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PRO00040486

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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