Cardiometabolic effects of gender-affirming hormone therapy in transgender adolescents

项目摘要/摘要 在美国，大约0.7%-1.8%或约275,000名年轻人认为自己是变性人，这个数字可能还会增加 更好地认识到这种情况。性别肯定激素疗法(GAHT)，试图更多地 使外貌与确定的性别相一致，是变性人的主要医疗干预措施 人类，并被认为是医学上必要的。GAHT与心脏新陈代谢增加有关 变性人的风险(血压升高、血脂异常、胰岛素抵抗和内皮功能障碍) 成年人。虽然治疗标准已经演变为在青春期启动GAHT，但对 发生在青春期GAHT的心脏代谢变化，这是跨性青年最佳护理的关键差距。 这项提案首次使用最先进的技术，旨在表征新陈代谢和 发生在跨性青年中的心血管变化与GAHT的启动。我们假设改变后的 荷尔蒙环境是变性人青年心脏代谢风险增加的主要驱动因素。发起了 睾酮或雌激素将对胰岛素抵抗的标志物、血脂谱、血管 健康和内皮功能。变性人将接受两次检查：在GAHT开始之前和 六个月后，当激素替代策略通常导致激素水平与顺式激素水平相当时- 性别成年人。使用高胰岛素-正常血糖钳夹技术和稳定的同位素示踪剂，精确 外周和肝脏的胰岛素敏感性测量将被量化和分析，以隔离 外源性激素(睾酮和雌激素)。其他代谢指标将从口服中确定 糖耐量试验(全身胰岛素敏感性、胰岛素生成指数)和Bod Pod(身体成分) 在基线和6个月时进行。管道水平的内皮功能将通过流量介导法进行评估 肱动脉的血管扩张和微血管内皮功能(皮肤血流量)将通过以下方式确定 在治疗前和治疗6个月后，用激光多普勒血流仪对前臂局部皮肤进行加热。随着时间的推移, 我们将比较变性人和顺性人的心脏代谢变化。 控制。这些新颖和创新的研究将阐明早期代谢和血管变化 伴随着GAHT，使人们能够更明智地了解跨性青年的心脏代谢风险 正在接受治疗。这是我们知识中的一个关键缺口；一旦这些早期的变化可以被描述出来， 后续研究可以在更长的治疗轨迹上跟踪这些变化，并进行有效的干预 可以设计和评估减少不良代谢和心血管后果。

PROJECT SUMMARY / ABSTRACT In the US, approximately 0.7-1.8% or ~ 275,000 youth 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 cardiometabolic risk (increased blood pressure, dyslipidemia, insulin resistance, and endothelial dysfunction) in transgender adults. While treatment standards have evolved to initiate GAHT in adolescence, little is known about the cardiometabolic changes that occur with GAHT in adolescence, a critical gap in the optimal care of trans youth. For the first time using state-of-the-art techniques, this proposal aims to characterize the metabolic and cardiovascular changes that occur in trans youth with the initiation of GAHT. We hypothesize that the altered hormonal milieu is the major driver of increased cardiometabolic risk in transgender youth. The initiation of testosterone or estrogen will have characteristic effects on markers of insulin resistance, lipid profiles, vascular health, and endothelial function. Transgender subjects will be examined twice: prior to the initiation of GAHT and again six months later when hormone replacement strategies typically result in hormonal levels comparable to cis- gender adults. Using the hyperinsulinemic-euglycemic clamp technique with stable isotope tracers, precise peripheral and hepatic insulin sensitivity measures will be quantified and analyzed to isolate the effects of exogenous hormones (testosterone and estrogen). Additional metabolic metrics will be determined from oral glucose tolerance tests (whole-body insulin sensitivity, insulinogenic index) and Bod Pod (body composition) performed at baseline and six months. The conduit-level endothelial function will be assessed by flow-mediated vasodilation of the brachial artery, and microvascular endothelial function (skin blood flow) will be determined by local forearm skin heating with laser Doppler flowmetry, at baseline and after six months of GAHT. Over time, we will compare the cardiometabolic changes in transgender subjects to those of cisgender male and female controls. These novel and innovative studies will illuminate the early metabolic and vascular changes accompanying GAHT, enabling a more informed understanding of the cardiometabolic risks in trans youth undergoing treatment. This is a critical gap in our knowledge; once these early changes can be characterized, subsequent studies can track these changes over longer treatment trajectories, and effective interventions to reduce adverse metabolic and cardiovascular outcomes can be designed and evaluated.