Brain Health in Transgender Adults

Cerebral Blood Flow and Neurocognitive Performance in Adults Undergoing Gender-affirming Hormone Therapy

The purpose of this study is to test whether and how a person's brain changes in the first few months after starting gender affirming hormone therapy (GAHT). The investigators want to know if GAHT changes: 1) cerebral blood flow (CBF), 2) brain structure, connectivity, and cognitive task performance, and 3) neurocognitive function (memory, attention, executive function, processing speed). 36 male at birth and 36 female at birth participants will conduct baseline studies prior to GAHT, with a second identical set of study visits 4-6 months after GAHT begins.

Study Overview

• Status: Recruiting
• Conditions: Gender Dysphoria
• Intervention / Treatment: Device: Magnetic Resonance Imaging; Other: Cognition and Health Tests; Other: Optional Exercise Test

Detailed Description

The purpose of this study is to assess the effects of GAHT on cerebral structure and function. To this end, this study has three aims:

Aim 1: To identify if transgender males and females demonstrate changes in

• A) basal CBF and
• B) CBF responses to acute stress-particularly in areas involved in cognition, memory, and learning.

Aim 2: To identify if transgender adults will demonstrate significant changes in:

• A) overall brain structure,
• B) functional connectivity, and
• C) task activation.

Aim 3: To identify if neurocognitive function changes in transgender adults.

The investigators hypothesize that:

• Aim 1: Transgender females will demonstrate increased basal CBF and larger CBF responses to acute stress, particularly in areas involved in cognition, memory, and learning, whereas transgender males will display lower basal CBF and lower CBF responses to acute stress.
• Aim 2: Transgender patients will demonstrate significant changes in: a) overall brain structure, b) functional connectivity, and c) task activation.
• Aim 3: Neurocognitive function will increase in transgender females and decreases in transgender males, primarily in the domains of memory, attention, executive function, and processing speed.

• Study Type: Observational
• Enrollment (Estimated): 72

Contacts and Locations

• Study Contact: Name: Shawn Bolin, MS; Phone Number: 608-263-6308; Email: sbolin@wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • UW School of Medicine and Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Adults (18-45 years) undergoing gender affirming hormone therapy with their clinical health care team.

Description

Inclusion Criteria:

• intention to undergo GAHT

Exclusion Criteria:

• BMI greater than 40 kg/m2
• Age greater than 45 yrs
• Blood pressure greater than 140/90 (stage II hypertension)
• A current diagnosis of type II diabetes
• History of traumatic brain injury/concussion, stroke, or seizures
• Are post-menopausal
• Previously taken hormone therapy medications
• Self-reported pregnancy (no pregnancy test)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Male at birth undergoing GAHT with their Clinical Care Team	Device: Magnetic Resonance Imaging; Two MRI visits (baseline and after 4-6 months of continuous GAHT) will involve structural scans of the brain, scans while performing cognitive tasks, and a scan taken while responding to an inhaled CO2 stressor. This visit will take approximately 1.5 hours.; Other Names: MRI; Other: Cognition and Health Tests; Two cognition and health test trials (baseline and after 4-6 months of continuous GAHT) will involve a body composition scan to determine body fat percentage, muscle mass, and bone density. This will be followed by a set of cognitive tasks using the NIH Toolbox.; Other: Optional Exercise Test; Optional graded exercise test will be performed if the participant consents to this optional procedure (baseline and after 4-6months of continuous GAHT). to determine cardiorespiratory fitness. This test will be performed on a cycle ergometer, with a metabolic allowing for the measurement of maximal oxygen consumption via indirect calorimetry.
Female at birth undergoing GAHT with their Clinical Care Team	Device: Magnetic Resonance Imaging; Two MRI visits (baseline and after 4-6 months of continuous GAHT) will involve structural scans of the brain, scans while performing cognitive tasks, and a scan taken while responding to an inhaled CO2 stressor. This visit will take approximately 1.5 hours.; Other Names: MRI; Other: Cognition and Health Tests; Two cognition and health test trials (baseline and after 4-6 months of continuous GAHT) will involve a body composition scan to determine body fat percentage, muscle mass, and bone density. This will be followed by a set of cognitive tasks using the NIH Toolbox.; Other: Optional Exercise Test; Optional graded exercise test will be performed if the participant consents to this optional procedure (baseline and after 4-6months of continuous GAHT). to determine cardiorespiratory fitness. This test will be performed on a cycle ergometer, with a metabolic allowing for the measurement of maximal oxygen consumption via indirect calorimetry.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change Cerebral Blood Flow (CBF)	CBF at rest and in response to cognitive stressors.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Brain Structure	Grey matter and White matter volumes.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Brain Connectivity	Measured using MRI.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Cognitive Function: Flanker Inhibitory Control and Attention	NIH Toolbox to assess neurocognitive function. The Flanker test is a measure of executive function and is scored using a T-score where 100 is the average, higher scores indicate better performance.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Cognitive Function: Pattern Comparison Processing Speed Test	NIH Toolbox to assess neurocognitive function. The Pattern Comparison Processing Speed Test measures how many correct responses the participant has within 90 seconds. There is a maximum of 130 items.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Cognitive Function: List Sorting Working Memory Test	NIH Toolbox to assess neurocognitive function. The List Sorting Working Memory Test is a measure of recall and sorting. Participants scores reflect the number of items recalled and appropriately sorted up to 28 items maximum.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Cognitive Function: Dimensional Change Card Sort Test	NIH Toolbox to assess neurocognitive function. The Dimensional Change Card Sort Test measures accuracy: the number of accurate responses, up to a maximum of 40.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Cognitive Function: Picture Vocabulary Test	NIH Toolbox to assess neurocognitive function. The Picture Vocabulary Test has the participant hear a word and then pick from one of four pictures that best represents the word. It is scored using a T-score where 100 is the average, higher scores indicate better performance.	baseline and up to 6 months (after 4-6 months of continuous GAHT)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change Cerebral Blood Flow (CBF)	Changes in CBF in response to inhaled mixture of room air and CO2	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Changes in sex steroid concentrations		baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Body Composition	Dual-energy X-ray absorptiometry (DEXA)	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Blood Glucose	Glucose is a marker of metabolic health	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Insulin	Insulin is a marker of metabolic health.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Change in Cytokines	Cytokines are a marker of inflammation.	baseline and up to 6 months (after 4-6 months of continuous GAHT)
Optional Graded Exercise Test: VO2 Max	An optional graded exercise test will be performed to determine cardiorespiratory fitness. This test will be performed on a cycle ergometer, with a metabolic allowing for the measurement of maximal oxygen consumption via indirect calorimetry. This will be a ramped exercise test, starting at a wattage of 50W and increasing in difficulty by 1 watt every 2 seconds. The purpose of this is to begin at a low intensity and gradually increase the difficulty until exhaustion is reached.	baseline and up to 6 months (after 4-6 months of continuous GAHT)

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Investigators: Principal Investigator: William Schrage, PhD, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2025
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: May 28, 2026
• First Submitted That Met QC Criteria: May 28, 2026
• First Posted (Actual): June 3, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: brain health; Gender-Affirming Hormone Therapy
• Additional Relevant MeSH Terms: Mental Disorders; Sexual Dysfunctions, Psychological; Gender Dysphoria; Diagnostic Techniques and Procedures; Diagnosis; Tomography; Diagnostic Imaging; Magnetic Resonance Imaging
• Other Study ID Numbers: 2024-1861; Protocol Version 1/12/26 (Other Identifier: UW Madison); SOE/Kinesiology (Other Identifier: UW Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No