Back to resultsMechanisms and Interventions to Address Cardiovascular Risk of Gender-affirming Hormone Therapy in Trans Men
Primary Purpose
Hypertension, Hyperlipidemias
Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Atorvastatin
placebo
Sponsored by
About this trial
This is an interventional other trial for Hypertension
Eligibility Criteria
Inclusion Criteria:
- Two groups (n=10 each) of subjects will be recruited to complete this study: 1) trans men between 18 and 35 years; 2) cisgender women between 18 and 35 years (Controls). They will have a body mass index (BMI) 18-30 kg·m-2. Our subjects will be matched on BMI and IR, using hemoglobin A1c and Homeostatic Model Assessment of Insulin Resistance technique (HOMA-IR) in order to isolate testosterone effects from other co-morbidities that may impact BP, sympathetic activity or endothelial function. Subjects will have HbA1c of 4-5.9% and a HOMA-IR of 0.5-1.4 to be included in the study. 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 CV medications.
Exclusion Criteria:
- Subjects with the following histories or conditions will be excluded from the study:
Gynecologic: a. current or past estrogen-dependent neoplasia, b. unexplained vaginal bleeding, c. history of uterine fibroids, d. current pregnancy, e. known or suspected breast or uterine cancer, f. partial or complete hysterectomy.
Cardiac: a. myocardial infarction, ventricular tachycardia or fibrillation, b. angina, c. valvular disease (mitral insufficiency or stenosis, aortic insufficiency or stenosis), d. congestive heart failure, orthopnea, paroxysmal nocturnal dyspnea, e. current arrhythmias, f. prosthetic valves.
Pulmonary: a. current cigarette smokers, or pipe or cigar smokers, b. chronic obstructive pulmonary disease, c. adult asthma, d. dyspnea on exertion, e. current bronchitis, pneumonia, or tuberculosis, f. lung carcinoma, g. pulmonary embolus, h. deep vein thrombosis.
Vascular: a. claudications or history of peripheral vascular disease, b. abdominal or thoracic aortic aneurysm, or repair of same, c. cerebral aneurysm, vascular malformations, d. hypertension, systolic or diastolic, or strong family history of hypertension.
Gastrointestinal: a. GI malignancy, b. hepatitis or other liver disease, current, c. splenomegaly from any cause, d. Cholecystitis, e. current diverticulosis or diverticulitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, f. previous gastrointestinal surgery.
Infectious Disease: any ongoing intercurrent infection. Hematologic/Oncologic: a. receiving chemotherapy or radiation therapy, b. any metastatic malignancy, c. anemia (hematocrit < 35), d. thrombocytopenia or thrombocytosis, e. neutropenia, f. hematologic malignancy, g. bleeding dyscrasia.
Neurologic: a. history of cerebral vascular accident with any neurologic sequels, b. uncontrolled seizures (e.g., more than 1 seizure/year), c. transient ischemic attacks, d. dementia, e. neurologic conditions producing dyscoordination, peripheral neuropathy, or myopathy.
Endocrine: a. diabetes mellitus, b. any untreated endocrinopathy. Renal: a. chronic renal diseases, b. any history of renal disease or impairment, c. current urinary tract infection.
Musculoskeletal: a. inflammatory arthritis history (e.g., rheumatoid, psoriatic, Reiters), b. any history of pathologic fractures, including vertebral compression fractures.
Pharmacologic: a. any illegal drug use, b. alcohol use greater than an average of 4 oz/day over 30 days, c. coumadin or heparin use.
Sites / Locations
- Yale School of Medicine
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
atorvastatin
Placebo
Arm Description
We are testing that the lipid sensitive statin, atorvastatin treatment will reduce low density lipoprotein cholesterone, sympathetic nerve activity, increase endothelium-dependent vasodilation and improve autonomic function in trans men, while having little impact on cis women.
We are testing that the placebo will have little effect on low density lipoprotein cholesterone, sympathetic nerve activity, endothelium-dependent vasodilation, autonomic function in trans men or cis women.
Outcomes
Primary Outcome Measures
flow mediated vasodilation (FMD)
FMD measures endothelial function, measured in % change from baseline arterial diameter after release following a short period of occlusion occlusion. The % change in diameter reflects the ability of the vessel to dilate in response to sheer stress induced by the flow following the release of occlusion. This reflects the function of the endothelium, or release of nitric oxide.
Muscle Sympathetic Nerve activity (MSNA)
measured using microneurography and expressed in bursts/min or bursts/100 heart beats
Cardiovagal baroreflex sensitivity (BRS)
This is determined as a function of change in R-R interval (from EKG) over systolic blood pressure during rest and regular breathing. Expressed in Units.
Mental Stress Test
While measuring sympathetic nervous system activity (SNS) with microneurography, we ask the subject to count backwards from 200 by 7. This increases SNS. Measured in bursts/min or burst/100 heart beats
Voluntary Breath-Hold
While measuring sympathetic nervous system activity (SNS) with microneurography, we ask the subject to hold breath as long as possible without straining. The subject does this twice, with a break in between. This increases SNS. Measured in bursts/min or burst/100 heart beats
Systolic Blood Pressure
SBP, measured in mmHg
Diastolic Blood Pressure
DBP, measured in mmHg
serum total cholesterol
Measured in ng/dl. Elevated total cholesterol can indicate dyslipidemia.
serum low density lipoprotein (LDL)-C
Measured in ng/dl. Elevated LDL-C can indicate dyslipidemia
serum high density lipoprotein (HDL-C)
Measured in ng/dl. Low HDL-C can indicate dyslipidemia
plasma endothelin-1, (S[ET-1])
endothelial health, increased ET-1 levels in the blood indicate damage to the endothelium
Secondary Outcome Measures
plasma Catecholamines
Measure of norepinephrine in pg/ml is a measure of whole body sympathetic nervous system outflow
serum estradiol (S[E2])
estrogen is measured in pg/ml. This should be suppressed in our trans subjects, and low in our cis subjects. In the latter, low estrogen should indicate the early follicular phase of the menstrual cycle.
serum progesterone (S[P4])
progesterone is measured in pg/ml. This should be suppressed in our trans subjects, and low in our cis subjects. In the latter, low progesterone should indicate the early follicular or ovulatory phases of the menstrual cycle.
serum sex hormone binding globulin (P[SHBG])
measured in pg/ml. This provides us with an indication of how much testosterone is free versus bound in the serum, and thus is available for biological function.
serum testosterone
measured in pg/ml. This indicates the level of testosterone in our trans men showing they are receiving treatment. It should be high in our trans men and low in our cis women subjects.
plasma creatinine
This is a measure of kidney function. Important for blood pressure regulation
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04922424
Brief Title
Mechanisms and Interventions to Address Cardiovascular Risk of Gender-affirming Hormone Therapy in Trans Men
Official Title
Mechanisms and Interventions to Address Cardiovascular Risk of Gender-affirming Hormone Therapy in Trans Men
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Withdrawn
Why Stopped
not funded
Study Start Date
September 30, 2022 (Anticipated)
Primary Completion Date
August 31, 2023 (Anticipated)
Study Completion Date
August 31, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No
5. Study Description
Brief Summary
Gender-identity differences are becoming increasingly diagnosed in the US and treatment with gender-affirming hormone therapy (GAHT) is associated with improved mental health outcomes. However, GAHT has been associated with cardiovascular risk in adult transgender patients, although mechanisms and treatments have not been explored. Understanding the cardiovascular effects and exploring the potential of a lipid sensitive statin as a potential treatment is important to optimizing safe treatment strategies for transgender men in mitigating this modifiable risk factor, and designing and implementing effective interventions.
Detailed Description
In the US approximately 1.4 million men identify as transgender, a number that is likely to increase with greater recognition of this condition. Gender affirming hormone therapy (GAHT), which attempts to more align the physical appearance with the identified gender, is the primary medical intervention for transgender people and is recognized as medically necessary. GAHT has been associated with increased cardiovascular risk (increased blood pressure, dyslipidemia, and endothelial dysfunction) in transgender men receiving androgens, however little is known about the mechanisms for these changes and few interventions have been proposed. We hypothesize that the altered hormonal milieu is the major driver of increased cardiovascular risk in trans men, and the initiation of testosterone will have effects on lipid profiles, blood pressure and endothelial function. In addition, androgen exposure within the female vascular system is associated with sympathetic nervous system dysregulation. We propose this dysregulation is mediated through rapid dyslipidemia associated with GAHT in trans men receiving androgens. The first aim of this proposal is to test the hypothesis that testosterone treatment in trans men increases sympathetic activation, blood pressure and endothelial dysfunction. Recent studies have demonstrated that vascular endothelial cells are crucial to the pathogenesis of inflammatory disease. Thus, the cholesterol lowering effects of certain statins appear to be mediated, in part, by their action on the endothelium. Important to these studies, HMG-CoA reductase inhibitors (i.e. lipid dependent statins) not only lower LDL-C, but improve both central sympathetic and peripheral microvascular function. Therefore, our second aim is to test the hypothesis that lipid dependent statin therapy will decrease sympathetic activation and improve endothelial function in trans men taking GAHT indicating that the increased sympathetic activity and endothelial dysfunction are mediated by the increased LDL-C with androgens. Trans men undergoing GAHT and cisgender female controls will be examined twice: at baseline, and again following 30 days of treatment with the lipid dependent statin, atorvastatin, in a randomized cross over design. Using microneurography, measures of sympathetic nerve activity (SNA) in response to stressors will be quantified and analyzed within- and between groups and cardiovascular metrics including beat to beat blood pressure and conduit-level endothelial function will be assessed at baseline and with atorvastatin treatment. These novel and innovative studies will illuminate the sympathetic and vascular changes that accompany GAHT, and our atorvastatin intervention will provide insight into the mechanism for these changes as well as provide a method to reduce these risks in trans men undergoing GAHT. This is a critical gap in our knowledge; once these early changes can be identified and quantified, subsequent studies can track these changes over longer trajectories of treatment.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Hyperlipidemias
7. Study Design
Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
Baseline testing, then each condition (group) will receive atorvastatin or placebo, followed by washout. Then receive the other condition.
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Participant, PI and RA will not know whether the participant is taking the atorvastatin or placebo. Supervising physician will know.
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
atorvastatin
Arm Type
Experimental
Arm Description
We are testing that the lipid sensitive statin, atorvastatin treatment will reduce low density lipoprotein cholesterone, sympathetic nerve activity, increase endothelium-dependent vasodilation and improve autonomic function in trans men, while having little impact on cis women.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
We are testing that the placebo will have little effect on low density lipoprotein cholesterone, sympathetic nerve activity, endothelium-dependent vasodilation, autonomic function in trans men or cis women.
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Intervention Description
Subjects will ingest placebo or ingest 20 mg atorvastatin for 30 days first. We will include 30 days of washout between treatments to minimize any potential carryover effects.
Intervention Type
Other
Intervention Name(s)
placebo
Intervention Description
Subjects will ingest placebo or ingest 20 mg atorvastatin for 30 days first. We will include 30 days of washout between treatments to minimize any potential
Primary Outcome Measure Information:
Title
flow mediated vasodilation (FMD)
Description
FMD measures endothelial function, measured in % change from baseline arterial diameter after release following a short period of occlusion occlusion. The % change in diameter reflects the ability of the vessel to dilate in response to sheer stress induced by the flow following the release of occlusion. This reflects the function of the endothelium, or release of nitric oxide.
Time Frame
30 minutes
Title
Muscle Sympathetic Nerve activity (MSNA)
Description
measured using microneurography and expressed in bursts/min or bursts/100 heart beats
Time Frame
2 hours
Title
Cardiovagal baroreflex sensitivity (BRS)
Description
This is determined as a function of change in R-R interval (from EKG) over systolic blood pressure during rest and regular breathing. Expressed in Units.
Time Frame
2 hours
Title
Mental Stress Test
Description
While measuring sympathetic nervous system activity (SNS) with microneurography, we ask the subject to count backwards from 200 by 7. This increases SNS. Measured in bursts/min or burst/100 heart beats
Time Frame
10 minutes
Title
Voluntary Breath-Hold
Description
While measuring sympathetic nervous system activity (SNS) with microneurography, we ask the subject to hold breath as long as possible without straining. The subject does this twice, with a break in between. This increases SNS. Measured in bursts/min or burst/100 heart beats
Time Frame
10 minutes
Title
Systolic Blood Pressure
Description
SBP, measured in mmHg
Time Frame
2 hours
Title
Diastolic Blood Pressure
Description
DBP, measured in mmHg
Time Frame
2 hours
Title
serum total cholesterol
Description
Measured in ng/dl. Elevated total cholesterol can indicate dyslipidemia.
Time Frame
5 minutes
Title
serum low density lipoprotein (LDL)-C
Description
Measured in ng/dl. Elevated LDL-C can indicate dyslipidemia
Time Frame
5 minutes
Title
serum high density lipoprotein (HDL-C)
Description
Measured in ng/dl. Low HDL-C can indicate dyslipidemia
Time Frame
5 minutes
Title
plasma endothelin-1, (S[ET-1])
Description
endothelial health, increased ET-1 levels in the blood indicate damage to the endothelium
Time Frame
5 minutes
Secondary Outcome Measure Information:
Title
plasma Catecholamines
Description
Measure of norepinephrine in pg/ml is a measure of whole body sympathetic nervous system outflow
Time Frame
5 minutes
Title
serum estradiol (S[E2])
Description
estrogen is measured in pg/ml. This should be suppressed in our trans subjects, and low in our cis subjects. In the latter, low estrogen should indicate the early follicular phase of the menstrual cycle.
Time Frame
5 minutes
Title
serum progesterone (S[P4])
Description
progesterone is measured in pg/ml. This should be suppressed in our trans subjects, and low in our cis subjects. In the latter, low progesterone should indicate the early follicular or ovulatory phases of the menstrual cycle.
Time Frame
5 minutes
Title
serum sex hormone binding globulin (P[SHBG])
Description
measured in pg/ml. This provides us with an indication of how much testosterone is free versus bound in the serum, and thus is available for biological function.
Time Frame
5 minutes
Title
serum testosterone
Description
measured in pg/ml. This indicates the level of testosterone in our trans men showing they are receiving treatment. It should be high in our trans men and low in our cis women subjects.
Time Frame
5 minutes
Title
plasma creatinine
Description
This is a measure of kidney function. Important for blood pressure regulation
Time Frame
5 minutes
10. Eligibility
Sex
All
Gender Based
Yes
Gender Eligibility Description
trans men, cis women
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Two groups (n=10 each) of subjects will be recruited to complete this study: 1) trans men between 18 and 35 years; 2) cisgender women between 18 and 35 years (Controls). They will have a body mass index (BMI) 18-30 kg·m-2. Our subjects will be matched on BMI and IR, using hemoglobin A1c and Homeostatic Model Assessment of Insulin Resistance technique (HOMA-IR) in order to isolate testosterone effects from other co-morbidities that may impact BP, sympathetic activity or endothelial function. Subjects will have HbA1c of 4-5.9% and a HOMA-IR of 0.5-1.4 to be included in the study. 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 CV medications.
Exclusion Criteria:
Subjects with the following histories or conditions will be excluded from the study:
Gynecologic: a. current or past estrogen-dependent neoplasia, b. unexplained vaginal bleeding, c. history of uterine fibroids, d. current pregnancy, e. known or suspected breast or uterine cancer, f. partial or complete hysterectomy.
Cardiac: a. myocardial infarction, ventricular tachycardia or fibrillation, b. angina, c. valvular disease (mitral insufficiency or stenosis, aortic insufficiency or stenosis), d. congestive heart failure, orthopnea, paroxysmal nocturnal dyspnea, e. current arrhythmias, f. prosthetic valves.
Pulmonary: a. current cigarette smokers, or pipe or cigar smokers, b. chronic obstructive pulmonary disease, c. adult asthma, d. dyspnea on exertion, e. current bronchitis, pneumonia, or tuberculosis, f. lung carcinoma, g. pulmonary embolus, h. deep vein thrombosis.
Vascular: a. claudications or history of peripheral vascular disease, b. abdominal or thoracic aortic aneurysm, or repair of same, c. cerebral aneurysm, vascular malformations, d. hypertension, systolic or diastolic, or strong family history of hypertension.
Gastrointestinal: a. GI malignancy, b. hepatitis or other liver disease, current, c. splenomegaly from any cause, d. Cholecystitis, e. current diverticulosis or diverticulitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, f. previous gastrointestinal surgery.
Infectious Disease: any ongoing intercurrent infection. Hematologic/Oncologic: a. receiving chemotherapy or radiation therapy, b. any metastatic malignancy, c. anemia (hematocrit < 35), d. thrombocytopenia or thrombocytosis, e. neutropenia, f. hematologic malignancy, g. bleeding dyscrasia.
Neurologic: a. history of cerebral vascular accident with any neurologic sequels, b. uncontrolled seizures (e.g., more than 1 seizure/year), c. transient ischemic attacks, d. dementia, e. neurologic conditions producing dyscoordination, peripheral neuropathy, or myopathy.
Endocrine: a. diabetes mellitus, b. any untreated endocrinopathy. Renal: a. chronic renal diseases, b. any history of renal disease or impairment, c. current urinary tract infection.
Musculoskeletal: a. inflammatory arthritis history (e.g., rheumatoid, psoriatic, Reiters), b. any history of pathologic fractures, including vertebral compression fractures.
Pharmacologic: a. any illegal drug use, b. alcohol use greater than an average of 4 oz/day over 30 days, c. coumadin or heparin use.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nina Stachenfeld
Organizational Affiliation
Yale School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Mechanisms and Interventions to Address Cardiovascular Risk of Gender-affirming Hormone Therapy in Trans Men
We'll reach out to this number within 24 hrs