Skeletal effects of early pubertal suppression and peer-concordant puberty timing in transgender and gender diverse youth

项目总结/摘要 跨性别和性别多样性（TGD）青年启动性别肯定的医学治疗，早在坦纳 第2阶段，使用促性腺激素释放激素激动剂（GnRHa）抑制青春期，时间可变 性别确认性激素（GAH）。在青春期和青年期达到峰值骨量， 在很大程度上决定了晚年与年龄有关的骨折。有令人信服的证据表明，治疗前的骨 TGD青年的骨密度（BMD）较低， 变性青年在青春期早期启动GnRHa的TGD青年的骨几何结构与 那些在青春期后期开始的人。所有已发表的关于TGD青年骨测量的纵向研究均 在16岁左右开始GAH（荷兰模型），没有研究描述TGD的骨骼轨迹 在青春期早期启动GnRHa并在14岁时遵循同龄人一致的青春期时间模型与GAH的青年 年本提案的目的是评估骨量、结构和 TGD青少年遵循同龄人一致的青春期时间模型，并评估 骨骼健康的决定因素。李博士将从她现有的队列中招募30名参与者 在GnRHa治疗前和治疗第一年期间进行了详细骨测量的青春期早期TGD青年。 她将利用双能X线吸收测量法测定GAH 3年期间的骨骼测量值 (DXA)量化BMD增量和BMD Z评分变化（目标1）。李博士将DXA测量与 用于骨结构和强度的高分辨率外周定量计算机断层扫描（HR-pQCT） 估计负重和非负重部位以及骨干部位的变化，以检查肌肉 质量和密度（目标2）。她发现青春期早期TGD青年治疗前低BMD与 低体力活动和握力是一个积极的预测失败的负荷。李医生会用大腿- 安装的三轴加速度计，用于测量身体活动的强度/持续时间/久坐时间和手部- 握力和膝关节伸展测力法测量等长力量，以制定未来的阈值目标 干预研究（目标3）。李博士组建了一个跨学科的导师团队， 专业知识，以实现这些目标，并接受培训，在骨内分泌和变性医学， 青少年DXA和HR-pQCT解释，生物力学负荷评估和肌肉力量测试， 队列研究实施和复杂的纵向数据分析。这项研究将产生 Lee博士开发更大的R 01前瞻性研究的数据，以跟踪骨骼轨迹，直到达到峰值骨量 达到为了优化治疗方案以减轻峰值骨量增加的潜在损害， 这可能会影响未来的骨折风险。李博士致力于骨骼发育的严格研究 在接受性别平等肯定医学治疗的TGD青年中， 她的长期目标是成为一名独立的医生，科学家，专注于TGD青年的骨骼健康。

PROJECT SUMMARY/ABSTRACT Transgender and gender diverse (TGD) youth initiate gender-affirming medical therapy as early as Tanner Stage 2 with gonadotropin-releasing hormone agonists (GnRHa) for puberty suppression, with variable timing of gender-affirming sex hormones (GAH). Peak bone mass, achieved during puberty and young adulthood, largely determines age-related fractures in later life. There is compelling evidence that pre-treatment bone mineral density (BMD) is low in TGD youth, and that peak bone mass attainment may be attenuated in transfeminine youth. TGD youth who initiate GnRHa in early puberty develop bone geometry distinct from those who start in late puberty. All published longitudinal studies on bone measures in TGD youth have initiated GAH around 16 years (Dutch Model), and no studies have described skeletal trajectories of TGD youth who initiate GnRHa in early puberty and follow a peer-concordant puberty-timing model with GAH by 14 years. The objective of this proposal is to evaluate the trajectory of bone mass, architecture, and strength in TGD youth who follow the peer-concordant puberty-timing model, and to assess the determinants of skeletal health in this population. Dr. Lee will enroll 30 participants from her existing cohort of early pubertal TGD youth who have had detailed bone measures prior to and during the first year of GnRHa. She will determine the skeletal measures during 3 years of GAH by utilizing dual-energy X-ray absorptiometry (DXA) to quantify BMD accrual and BMD Z-score changes (Aim 1). Dr. Lee will correlate DXA measures to high-resolution peripheral quantitative computed tomography (HR-pQCT) for bone architecture and strength estimate changes at weight-bearing and non-weight-bearing sites, and at diaphyseal sites to examine muscle mass and density (Aim 2). She found that low pre-treatment BMD in early pubertal TGD youth was associated with low physical activity and that grip strength was a positive predictor of failure load. Dr. Lee will utilize thigh- mounted tri-axial accelerometers to measure intensity/duration of physical activity/sedentary time and hand- grip and knee extension dynamometry to measure isometric strength to develop threshold targets for future intervention studies (Aim 3). Dr. Lee has assembled a cross-disciplinary mentor team with the necessary expertise to achieve these aims and receive training in the endocrinology of bone and transgender medicine, adolescent DXA and HR-pQCT interpretation, biomechanical load evaluation and muscle strength testing, cohort study implementation, and complex longitudinal data analysis. The proposed research will generate data for Dr. Lee to develop a larger R01 prospective study to follow skeletal trajectories until peak bone mass attainment in order to optimize treatment protocols to mitigate potential impairment in peak bone mass accrual, which could impact future fracture risk. Dr. Lee is committed to rigorous investigation of skeletal development in TGD youth receiving gender-affirming medical therapies and is confident that this K23 proposal will prepare her for her long-term goal of being an independent physician-scientist focused on bone health in TGD youth.