Clinical Manipulation of Testosterone and Its Impact on Dementia and Health

睾酮的临床操作及其对痴呆症和健康的影响

• 批准号: 10795680
• 负责人: RICHARD L HAUGER
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10795680
• 关键词: AR gene; Acceleration; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Androgens; Benefits and Risks; Biomedical Research; Brain; CAG repeat; Cardiovascular Diseases; Clinical; Clinical Data; Cognition; Cognitive; DNA Binding Domain; Data; Dementia; Development; Diabetes Mellitus; Disease; Disease Marker; Disease Progression; Early Intervention; Effectiveness; Functional disorder; Genetic; Genetic Risk; Health; Health Care Costs; Healthcare; Healthcare Systems; Hormone replacement therapy; Hypogonadism; Impaired cognition; Individual; Intervention; Knowledge; Length; Life; Ligand Binding Domain; Link; Malignant neoplasm of prostate; Medical; Medical Records; Medicine; Modeling; Motion; Mutation; Nature; Onset of illness; Outcome; Pathway interactions; Patients; Peripheral; Phase; Play; Precipitating Factors; Predisposition; Process; Prostate Cancer therapy; Recording of previous events; Recurrence; Relative Risks; Reporting; Research; Resources; Risk; Risk Factors; Role; Sample Size; Symptoms; System; Testing; Testosterone; Treatment Efficacy; Variant; Veterans; age related; androgen deprivation therapy; androgen sensitive; cognitive function; cohort; comorbidity; dementia risk; design; epidemiology study; evidence base; experimental study; hormone sensitivity; improved; innovation; insight; interest; male; men; middle age; mild cognitive impairment; military veteran; novel; older men; pre-clinical; precision medicine; programs; randomized, controlled study; response; success; testosterone replacement therapy; treatment center

The number of veterans with Alzheimer’s disease (AlzD) is dramatically increasing. Testosterone is hypothesized to have an important role in risk, onset, and progression of AlzD in men. Testosterone deficiency prior to AlzD onset can promote AlzD pathophysiology during the preclinical phase when interventions may have the greatest success. Androgen deprivation therapy (ADT) for prostate cancer and testosterone replacement therapy (TRT) for age-related hypogonadism that directly target testosterone levels provide valuable opportunities to examine the impact of this androgen on the risk of developing AlzD, its prodromal condition mild cognitive impairment (MCI), and co-morbid health conditions. In the proposed study, we will utilize genetic and clinical data from the Million Veteran Program (MVP) to determine the impact of low testosterone, ADT, and TRT on the relative risk for MCI and AlzD. We hypothesize that the long-term impact of low testosterone, ADT, and TRT will be regulated by polygenic risk for AlzD and variation in the androgen receptor (AR) gene. These genetic factors represent critical, pre-existing markers of disease vulnerability and hormone sensitivity that have yet to be incorporated into research on protective and beneficial effects of testosterone on cognition and health. In our study, we will first determine if the risks of MCI, AlzD, and co- morbid medical disorders that promote dementia are increased by low testosterone levels in the MVP cohort. Next, we will determine if the clinical manipulation of testosterone levels is associated with differences in risks for MCI and AlzD. We hypothesize that individuals who undergo ADT will be at increased risk for MCI, AlzD and co-morbid health conditions relative to men with a history of prostate cancer but who have not been treated with ADT. We further hypothesize that men who receive TRT will be at decreased risks for these same conditions relative to men with low testosterone who do not receive hormone replacement therapy. We will next test whether pre-existing genetic risk for AlzD modifies the impact of testosterone-centered treatments on MCI and AlzD. We hypothesize that the observed effects of ADT and TRT on the cognitive and health outcomes will be greater in individuals at greater genetic risk for AlzD. Finally, we will determine whether genetically driven changes in androgen sensitivity due to CAG repeat length or ligand and DNA binding domain mutations regulate the long-term risks and benefits of ADT and TRT. We hypothesize that a more sensitive variant of the AR gene will confer greater risk for MCI and AlzD following ADT. Furthermore, we hypothesize that more androgen-sensitive individuals will benefit more from TRT, and will therefore show a reduced risk for MCI and AlzD. With its large sample size, extensive genetic data, and curated medical record data, the MVP represents an ideal resource with which to explore impact of testosterone-centered treatments on dementia risk, and provide a proof-of-principle model of genetically informed precision medicine. By evaluating the long- term risks and benefits of ADT and TRT on cognitive health, in the context of a genetically informative design, the proposed study will provide valuable insights into the role of testosterone as a risk factor for MCI and AlzD, and increase our understanding of a critical AlzD-related pathway that may be responsive to intervention. The present study will also shed light on the long-term risks and benefits associated with ADT and TRT, and clarify whether these treatments, which are efficacious in certain contexts, set in motion or delay pathophysiological processes that result in the emergence of AlzD symptoms in men. Finally, we will determine if our hypothesis driven, genetically informed study investigating underlying genetic risk (i.e., the polygenic risk for AlzD) and genetically determined treatment sensitivity (i.e., variation within the AR gene) can improve treatment efficacy and evidence-based usage of TRT and reduce detrimental outcomes of ADT. We believe our study is ideal for the MVP, and will demonstrate effectiveness of the broader program for biomedical research and the advancement of personalized/precision medicine.

患有阿尔茨海默病（AlzD）的退伍军人人数正在急剧增加。睾酮是 假设在男性AlzD的风险、发病和进展中具有重要作用。睾酮缺乏 在临床前阶段，当干预措施可能 取得了最大的成功。前列腺癌的雄激素剥夺疗法（ADT）与睾酮 直接针对睾酮水平的年龄相关性性腺功能减退症的替代疗法（TRT）提供了 研究这种雄激素对发展AlzD风险的影响的宝贵机会， 轻度认知障碍（MCI）和共病健康状况。在拟议的研究中，我们将 利用来自百万退伍军人计划（MVP）的遗传和临床数据来确定低风险的影响。 睾酮、ADT和TRT对MCI和AlzD相对风险的影响。我们假设长期的影响 低睾酮、ADT和TRT将受AlzD多基因风险和雄激素变异的调节。 受体（AR）基因。这些遗传因素代表了疾病易感性的重要的、预先存在的标志， 激素敏感性，尚未纳入研究的保护和有益的影响， 睾酮对认知和健康的影响在我们的研究中，我们将首先确定MCI、AlzD和合并症的风险是否与 在MVP组群中，促进痴呆的病态医学疾病因低睾酮水平而增加。 接下来，我们将确定临床上对睾酮水平的操纵是否与风险的差异有关。 治疗轻度认知障碍和阿尔茨海默病我们假设接受ADT治疗的个体发生MCI、AlzD的风险增加， 与有前列腺癌病史但未接受过前列腺癌治疗的男性相比， 用ADT治疗。我们进一步假设，接受TRT的男性将降低这些相同的风险， 与没有接受激素替代疗法的低睾酮男性相比，我们将 下一个测试是否预先存在的遗传风险AlzD修改睾酮为中心的治疗的影响， MCI和AlzD。我们假设ADT和TRT对认知和健康的影响 结果将更大的个体在更大的遗传风险为阿尔茨海默病。最后，我们将确定 由于CAG重复序列长度或配体和DNA结合结构域导致的遗传驱动的雄激素敏感性变化 突变调节ADT和TRT的长期风险和益处。我们假设一个更敏感的 AR基因的变异将赋予ADT后MCI和AlzD更大的风险。此外，我们假设 雄激素敏感的个体从TRT中获益更多，因此会降低患 MCI和AlzD。凭借其大样本量，广泛的遗传数据和精心策划的医疗记录数据，MVP 是探索以睾酮为中心的治疗对痴呆症的影响的理想资源 风险，并提供一个基于遗传信息的精准医学的原理验证模型。通过评估长期- 在遗传信息设计的背景下，ADT和TRT对认知健康的长期风险和获益， 这项研究将为睾酮作为MCI和AlzD的危险因素的作用提供有价值的见解， 并增加我们对可能对干预反应的关键AlzD相关途径的理解。的 本研究还将阐明ADT和TRT相关的长期风险和获益，并阐明 这些在某些情况下有效的治疗是否启动或延迟了病理生理学， 导致男性出现AlzD症状的过程。最后，我们将确定我们的假设 受驱动的、遗传学方面知情的研究，调查潜在的遗传风险（即，AlzD的多基因风险）和 基因决定的治疗敏感性（即，AR基因内的变异）可以提高治疗效果 以证据为基础的TRT使用和减少ADT的有害结果。我们相信我们的研究是理想的， MVP，并将证明更广泛的生物医学研究计划的有效性， 个性化/精准医疗的进步。

项目成果

Prevalence, Morbidity, and Mortality of 1,609 Men with Sex Chromosome Aneuploidy: Results from the Diverse Million Veteran Program Cohort.

1,609 名性染色体非整倍体男性的患病率、发病率和死亡率：来自多元化百万退伍军人计划队列的结果。

• DOI: 10.1101/2023.07.15.23292710
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Davis,ShanleeM;Teerlink,Craig;Lynch,JulieA;Gorman,BryanR;Pagadala,Meghana;Liu,Aoxing;Panizzon,MatthewS;Merritt,VictoriaC;Genovese,Giulio;Pyarajan,Saiju;Ross,JudithL;Hauger,RichardL
• 通讯作者: Hauger,RichardL

Genetic risk and likelihood of prostate cancer detection on first biopsy by ancestry.

首次活检时检测出前列腺癌的遗传风险和可能性。

• DOI: 10.1093/jnci/djae002
• 发表时间: 2024
• 期刊: Journal of the National Cancer Institute
• 作者: Lee,KyungMin;Nelson,Tyler;Bryant,Alex;Teerlink,Craig;Gulati,Roman;Pagadala,Meghana;Tcheandjieu,Catherine;Pridgen,KathrynM;DuVall,ScottL;Yamoah,Kosj;Vassy,JasonL;Seibert,TylerM;Hauger,Richard;Rose,BrentS;Lynch,JulieA
• 通讯作者: Lynch,JulieA

A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity.

• DOI: 10.3389/fmed.2022.774773
• 发表时间: 2022
• 期刊: Frontiers in medicine
• 影响因子: 3.9

Agent Orange exposure and prostate cancer risk in the Million Veteran Program.

百万退伍军人计划中的橙剂暴露和前列腺癌风险。

• DOI: 10.1101/2023.06.14.23291413
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Lui,AsonaJ;Pagadala,MeghanaS;Zhong,AllisonY;Lynch,Julie;Karunamuni,Roshan;Lee,KyungMin;Plym,Anna;Rose,BrentS;Carter,Hannah;Kibel,AdamS;DuVall,ScottL;Gaziano,JMichael;Panizzon,MatthewS;Hauger,RichardL;Seibert,TylerM
• 通讯作者: Seibert,TylerM