Mechanisms of Blood Pressure Dysfunction in Transmen Receiving Testosterone
Primary Purpose
Transgender Men, Blood Pressure, Hyperandrogenism
Status
Withdrawn
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Trans men
Sponsored by
About this trial
This is an interventional basic science trial for Transgender Men focused on measuring transgender, baroreflex, testosterone
Eligibility Criteria
Inclusion Criteria:
- Both groups (trans men and cisgender women) must be healthy and non-smoking. Control participants must be cisgender women with regular menses every 26-34 days. Trans men participants must be currently receiving testosterone for gender affirming hormone therapy where physiologic doses of exogenous Dihydrotestosterone have been administered (via injection or transdermal application) for at least 3 months as prescribed by their local endocrine provider as part of their clinically indicated hormone therapy. Doses can vary depending on the size and goals of each patient, but blood testosterone will be between 400-1000 ng/dl.
Exclusion Criteria:
- Subjects who smoke, have diabetes, or BP>140/90 will be excluded.
- Subjects will not be taking medications during the study, including any insulin-sensitizing or cardiovascular medications.
- Subjects are excluded if they have lost > 5 kg of weight within the past 6 months or perform high-intensity exercise > 3 times/week.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
No Intervention
Arm Label
Trans men
control
Arm Description
transgender men taking physiologic doses of testosterone for gender affirming hormone therapy
cisgender women not receiving testosterone and with normal sex hormone levels
Outcomes
Primary Outcome Measures
Muscle Sympathetic Nerve Activity (MSNA)
MSNA is recorded continuously at rest and during O/LBNP protocols with a tungsten microelectrode (0.2 diameters insulated shaft tapered to an uninsulated tip of ~1-5 μm) inserted percutaneously into the median nerve. Multiunit, postganglionic MSNA is distinguished from other sources of nerve activity by the presence of spontaneous pulse synchronous bursts, increased activity when the subject holds their breath or clenches their first (stretches forearm muscles around median nerve), or if activity does not change when the skin is stimulated by light brushing or stroking (indicates lack of skin nerve activity). Bursts of MSNA at rest and during LBNP are quantified as total activity (AU/min), burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats). The MSNA burst incidence is expressed in bursts/100 heartbeats to normalize for differences in heart rate among subjects.
Systolic Blood Pressure (SBP)
SBP is measured continuously with a Finometer beat-to-beat blood pressure measurement system at rest and during O/LBNP protocols. Units are mm Hg.
Diastolic Blood Pressure (DBP)
DBP is measured continuously with a Finometer beat-to-beat blood pressure measurement system at rest and during O/LBNP protocols. Units are mm Hg.
Mean Arterial Pressure (MAP)
MAP at rest and during O/LBNP protocols is calculated as 1/3(SBP-DBP)+DBP using the beat-to-beat SBP and DBP measurements taken with the Finometer system. Units are mm Hg.
Sympathetic Baroreflex (BR) Gain
Sympathetic BR gain is used as an index of sympathetic (neural) control of blood pressure, where gain is determined by the slope of the linear relationship between MSNA (burst/100 heartbeats) and DBP (mm Hg) at rest and during LBNP. The relationship produces a negative slope in that for a given subject, when DBP falls below the normal level sustained at rest, sympathetic activity increases to restore DBP back to that normal level. Thus, more MSNA bursts are observed at lower levels of DBP and vice versa. A steeper (more negative) slope suggests greater sensitivity of the baroreceptors to changes in blood pressure, and thereby more effective sympathetic control of blood pressure. A flatter slope suggests impaired BR sensitivity and blood pressure dysfunction, which is expected for the trans men group compared to cisgender women controls.
Frequency in the Neural Cardiovascular Control
The frequency of SBP, DBP and heart rate during OLBNP is analyzed in Matlab in a linear time-invariant system (LTI) framework. Heart rate and BP measures taken during OLBNP are low-pass filtered (0.05 Hz estimated example) and corrected for end-effects using a Hamming window. The derived impulse responses (IRs) are 1/3rd octave smoothed before calculating the frequency power spectra (0.001-0.05 Hz estimated example). The power of DBP and SBP at the OLBNP frequency are anticipated to be independently inversely related to the efficiency of BP control. Further, the difference in heart rate and SBP, and in heart rate and DBP, power at those frequencies reflects the degree of autonomic function, analogous to baroreflex gain.
Electrocardiogram (ECG)
A 3-lead ECG is continuously recorded at rest and during the O/LBNP protocols. The R-wave of the QRS complex of the ECG recording will be used for measures of pulse interval by determining the amount of time in seconds between the R-waves of 2 consecutive QRS complexes.
Secondary Outcome Measures
Brachial Artery Mean Blood Flow Velocity
Mean blood flow velocity in the brachial artery will be examined at rest and during LBNP using Doppler ultrasound velocimetry. Blood flow velocity spectra and arterial diameter are measured simultaneously with a Doppler probe and SonoScape S2 ultrasound system. The brachial artery is imaged with a 6.0-MHz linear array probe positioned at a 45° angle over the skin at the distal one-third of the upper arm. Brachial blood flow is expected to decrease as the level of LBNP increases and induces a greater orthostatic challenge. For example, blood flow would be highest at the -10LBNP stage and continually decrease during the following stages of -20, -30 and finally -40LBNP, where blood flow would be the lowest.
Cardiovagal Baroreflex (BR) Gain
Cardiovagal BR gain is determined by the slope of the linear relationship between R-R Interval (seconds) and SBP (mm Hg) at rest and during LBNP. R-R Intervals are obtained from the ECG recording and SBP is obtained from the beat-to-beat measures taken by the Finometer.
Full Information
NCT ID
NCT04524325
First Posted
August 17, 2020
Last Updated
October 31, 2022
Sponsor
Yale University
Collaborators
The John B. Pierce Laboratory
1. Study Identification
Unique Protocol Identification Number
NCT04524325
Brief Title
Mechanisms of Blood Pressure Dysfunction in Transmen Receiving Testosterone
Official Title
Mechanisms of Blood Pressure Dysfunction in Transmen Receiving Testosterone
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Withdrawn
Why Stopped
Funding never received.
Study Start Date
January 1, 2023 (Anticipated)
Primary Completion Date
July 1, 2023 (Anticipated)
Study Completion Date
June 30, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
The John B. Pierce Laboratory
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this research is to explore the effects of chronic androgen exposure on sympathetic nervous system activity (SNSA) and baroreflex control of blood pressure responses in transgender men (trans men) taking gender affirming hormone therapy (HT). Blood pressure, baroreflex gain, and frequency of sympathetic responses to changes in blood pressure will be assessed in trans men and a control group of cisgender women. To fully understand HT effects on blood pressure regulation in trans men, it is crucial to understand how both SNSA, and the pattern of SNSA, can be influenced by high levels of androgen exposure in the female cardiovascular system, as well as how the two regulatory components may interact.
Detailed Description
The purpose of this research is to study how testosterone affects blood pressure control in trans men. High testosterone levels are detrimental to the female cardiovascular system in that higher levels are associated with increased blood pressure. Humans control blood pressure in the autonomic nervous system via the baroreflex mechanism. The arterial baroreflex is a key autonomic homeostatic mechanism involved in maintaining arterial blood pressure, and gain of the baroreflex is used as a measure of the sensitivity of sympathetic responses that act to restore acute blood pressure fluctuations. This autonomic regulation of blood pressure is also characterized by rhythmic activity (changes in cardiac frequency), which can be observed by recording sympathetic nerve traffic. When the female cardiovascular system is exposed to elevated androgens, baroreflex gain is impaired, and blood control is less efficient during an orthostatic challenge. However, to best understand the effect of a given stimulus on autonomic function, changes in frequency of the SNSA response must also be quantified in addition to the gain. Sympathetic control of arterial blood pressure is most effective in a narrow frequency range, and if this frequency range for responsiveness should narrow further, control of arterial blood pressure becomes less efficient and presents as dysfunction. The central hypothesis for this research is that dysregulation of blood pressure in trans men taking testosterone for gender affirming HT is a function of both reduced baroreflex gain and narrowed frequency-dependent relationship between arterial pressure and peripheral sympathetic vascular responsiveness. Specifically, these studies test the hypothesis that androgen supplementation with HT is associated with 1) lower baroreflex gain during a lower body negative pressure (LBNP) challenge, and 2) a narrowed response frequency range that precedes impaired sympathetic vascular response dynamics in trans men compared to control cisgender women.
Study procedures include an oral glucose tolerance test (OGTT), microneurography of the median nerve in the forearm to assess SNSA, and 2 LBNP challenges designed to examine baroreflex gain during static LBNP and then the frequency of SNSA during oscillating LBNP (OLBNP). Participants complete 3 visits for this study. Visit 1 is for informed consent procedures; Visit 2 is a pre-screening visit to complete the OGTT; Visit 3 is for experimental testing to assess gain and the frequency range. Blood pressure, heart rate and muscle SNSA (MSNA) are measured during LBNP and OLBNP. MSNA is recorded using 2 microelectrodes inserted through the skin of the forearm to record activity (firing) of the median nerve. Blood samples are taken via IV placement to measure insulin and glucose during the OGTT for Visit 2, and then sex hormones and catecholamines during Visit 3. Results from the group of young trans men will be compared to a control group of cisgender women matched for age and body mass index.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Transgender Men, Blood Pressure, Hyperandrogenism
Keywords
transgender, baroreflex, testosterone
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
There is 1 group of trans men (n=20) and 1 group of cisgender women (n=20). Study procedures, protocols, and measurements will be the same for both groups and performed and/or taken in a similar time period.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Trans men
Arm Type
Active Comparator
Arm Description
transgender men taking physiologic doses of testosterone for gender affirming hormone therapy
Arm Title
control
Arm Type
No Intervention
Arm Description
cisgender women not receiving testosterone and with normal sex hormone levels
Intervention Type
Other
Intervention Name(s)
Trans men
Intervention Description
We are studying the effects of testosterone taken by trans men on mechanisms of blood pressure control and comparing those results to cisgender women that have normal (ie lower) testosterone levels.
Primary Outcome Measure Information:
Title
Muscle Sympathetic Nerve Activity (MSNA)
Description
MSNA is recorded continuously at rest and during O/LBNP protocols with a tungsten microelectrode (0.2 diameters insulated shaft tapered to an uninsulated tip of ~1-5 μm) inserted percutaneously into the median nerve. Multiunit, postganglionic MSNA is distinguished from other sources of nerve activity by the presence of spontaneous pulse synchronous bursts, increased activity when the subject holds their breath or clenches their first (stretches forearm muscles around median nerve), or if activity does not change when the skin is stimulated by light brushing or stroking (indicates lack of skin nerve activity). Bursts of MSNA at rest and during LBNP are quantified as total activity (AU/min), burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats). The MSNA burst incidence is expressed in bursts/100 heartbeats to normalize for differences in heart rate among subjects.
Time Frame
3 hours
Title
Systolic Blood Pressure (SBP)
Description
SBP is measured continuously with a Finometer beat-to-beat blood pressure measurement system at rest and during O/LBNP protocols. Units are mm Hg.
Time Frame
3 hours
Title
Diastolic Blood Pressure (DBP)
Description
DBP is measured continuously with a Finometer beat-to-beat blood pressure measurement system at rest and during O/LBNP protocols. Units are mm Hg.
Time Frame
3 hours
Title
Mean Arterial Pressure (MAP)
Description
MAP at rest and during O/LBNP protocols is calculated as 1/3(SBP-DBP)+DBP using the beat-to-beat SBP and DBP measurements taken with the Finometer system. Units are mm Hg.
Time Frame
3 hours
Title
Sympathetic Baroreflex (BR) Gain
Description
Sympathetic BR gain is used as an index of sympathetic (neural) control of blood pressure, where gain is determined by the slope of the linear relationship between MSNA (burst/100 heartbeats) and DBP (mm Hg) at rest and during LBNP. The relationship produces a negative slope in that for a given subject, when DBP falls below the normal level sustained at rest, sympathetic activity increases to restore DBP back to that normal level. Thus, more MSNA bursts are observed at lower levels of DBP and vice versa. A steeper (more negative) slope suggests greater sensitivity of the baroreceptors to changes in blood pressure, and thereby more effective sympathetic control of blood pressure. A flatter slope suggests impaired BR sensitivity and blood pressure dysfunction, which is expected for the trans men group compared to cisgender women controls.
Time Frame
3 hours
Title
Frequency in the Neural Cardiovascular Control
Description
The frequency of SBP, DBP and heart rate during OLBNP is analyzed in Matlab in a linear time-invariant system (LTI) framework. Heart rate and BP measures taken during OLBNP are low-pass filtered (0.05 Hz estimated example) and corrected for end-effects using a Hamming window. The derived impulse responses (IRs) are 1/3rd octave smoothed before calculating the frequency power spectra (0.001-0.05 Hz estimated example). The power of DBP and SBP at the OLBNP frequency are anticipated to be independently inversely related to the efficiency of BP control. Further, the difference in heart rate and SBP, and in heart rate and DBP, power at those frequencies reflects the degree of autonomic function, analogous to baroreflex gain.
Time Frame
0.5 hours
Title
Electrocardiogram (ECG)
Description
A 3-lead ECG is continuously recorded at rest and during the O/LBNP protocols. The R-wave of the QRS complex of the ECG recording will be used for measures of pulse interval by determining the amount of time in seconds between the R-waves of 2 consecutive QRS complexes.
Time Frame
3 hours
Secondary Outcome Measure Information:
Title
Brachial Artery Mean Blood Flow Velocity
Description
Mean blood flow velocity in the brachial artery will be examined at rest and during LBNP using Doppler ultrasound velocimetry. Blood flow velocity spectra and arterial diameter are measured simultaneously with a Doppler probe and SonoScape S2 ultrasound system. The brachial artery is imaged with a 6.0-MHz linear array probe positioned at a 45° angle over the skin at the distal one-third of the upper arm. Brachial blood flow is expected to decrease as the level of LBNP increases and induces a greater orthostatic challenge. For example, blood flow would be highest at the -10LBNP stage and continually decrease during the following stages of -20, -30 and finally -40LBNP, where blood flow would be the lowest.
Time Frame
3 hours
Title
Cardiovagal Baroreflex (BR) Gain
Description
Cardiovagal BR gain is determined by the slope of the linear relationship between R-R Interval (seconds) and SBP (mm Hg) at rest and during LBNP. R-R Intervals are obtained from the ECG recording and SBP is obtained from the beat-to-beat measures taken by the Finometer.
Time Frame
3 hours
10. Eligibility
Sex
Female
Gender Based
Yes
Gender Eligibility Description
Transgender men will be recruited for participating in the experimental group; cisgender women will be recruited for participation in the control group.
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Both groups (trans men and cisgender women) must be healthy and non-smoking. Control participants must be cisgender women with regular menses every 26-34 days. Trans men participants must be currently receiving testosterone for gender affirming hormone therapy where physiologic doses of exogenous Dihydrotestosterone have been administered (via injection or transdermal application) for at least 3 months as prescribed by their local endocrine provider as part of their clinically indicated hormone therapy. Doses can vary depending on the size and goals of each patient, but blood testosterone will be between 400-1000 ng/dl.
Exclusion Criteria:
Subjects who smoke, have diabetes, or BP>140/90 will be excluded.
Subjects will not be taking medications during the study, including any insulin-sensitizing or cardiovascular medications.
Subjects are excluded if they have lost > 5 kg of weight within the past 6 months or perform high-intensity exercise > 3 times/week.
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
Mechanisms of Blood Pressure Dysfunction in Transmen Receiving Testosterone
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