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Mechanisms and Interventions to Address Cardiovascular Risk of Gender-affirming Hormone Therapy in Trans Men

2022년 10월 31일 업데이트: Yale University
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.

연구 개요

상태

빼는

정황

개입 / 치료

상세 설명

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.

연구 유형

중재적

단계

  • 1단계

연락처 및 위치

이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.

연구 장소

  • 미국
    • Connecticut
      • New Haven, Connecticut, 미국, 06519
        • Yale School of Medicine

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

18년 (성인)

건강한 자원 봉사자를 받아들입니다

예

연구 대상 성별

모두

설명

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.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

  • 주 목적: 다른
  • 할당: 무작위
  • 중재 모델: 크로스오버 할당
  • 마스킹: 삼루타

무기와 개입

참가자 그룹 / 팔
개입 / 치료
실험적: atorvastatin
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.
의약품: Atorvastatin
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.
위약 비교기: Placebo
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.
다른: placebo
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

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
측정값 설명
기간
flow mediated vasodilation (FMD)
기간: 30 minutes
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.
30 minutes
Muscle Sympathetic Nerve activity (MSNA)
기간: 2 hours
measured using microneurography and expressed in bursts/min or bursts/100 heart beats
2 hours
Cardiovagal baroreflex sensitivity (BRS)
기간: 2 hours
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.
2 hours
Mental Stress Test
기간: 10 minutes
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
10 minutes
Voluntary Breath-Hold
기간: 10 minutes
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
10 minutes
Systolic Blood Pressure
기간: 2 hours
SBP, measured in mmHg
2 hours
Diastolic Blood Pressure
기간: 2 hours
DBP, measured in mmHg
2 hours
serum total cholesterol
기간: 5 minutes
Measured in ng/dl. Elevated total cholesterol can indicate dyslipidemia.
5 minutes
serum low density lipoprotein (LDL)-C
기간: 5 minutes
Measured in ng/dl. Elevated LDL-C can indicate dyslipidemia
5 minutes
serum high density lipoprotein (HDL-C)
기간: 5 minutes
Measured in ng/dl. Low HDL-C can indicate dyslipidemia
5 minutes
plasma endothelin-1, (S[ET-1])
기간: 5 minutes
endothelial health, increased ET-1 levels in the blood indicate damage to the endothelium
5 minutes

2차 결과 측정

결과 측정
측정값 설명
기간
plasma Catecholamines
기간: 5 minutes
Measure of norepinephrine in pg/ml is a measure of whole body sympathetic nervous system outflow
5 minutes
serum estradiol (S[E2])
기간: 5 minutes
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.
5 minutes
serum progesterone (S[P4])
기간: 5 minutes
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.
5 minutes
serum sex hormone binding globulin (P[SHBG])
기간: 5 minutes
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.
5 minutes
serum testosterone
기간: 5 minutes
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.
5 minutes
plasma creatinine
기간: 5 minutes
This is a measure of kidney function. Important for blood pressure regulation
5 minutes

공동 작업자 및 조사자

여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.

스폰서

Yale University

수사관

  • 수석 연구원: Nina Stachenfeld, Yale School of Medicine

연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작 (예상)

2022년 9월 30일

기본 완료 (예상)

2023년 8월 31일

연구 완료 (예상)

2023년 8월 31일

연구 등록 날짜

최초 제출

2021년 6월 4일

QC 기준을 충족하는 최초 제출

2021년 6월 4일

처음 게시됨 (실제)

2021년 6월 10일

연구 기록 업데이트

마지막 업데이트 게시됨 (실제)

2022년 11월 3일

QC 기준을 충족하는 마지막 업데이트 제출

2022년 10월 31일

마지막으로 확인됨

2022년 10월 1일

추가 정보

이 연구와 관련된 용어

추가 관련 MeSH 약관

기타 연구 ID 번호

  • 2000030176

약물 및 장치 정보, 연구 문서

미국 FDA 규제 의약품 연구

예

미국 FDA 규제 기기 제품 연구

아니

미국에서 제조되어 미국에서 수출되는 제품

예

이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .

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