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) 的退伍军人数量正在急剧增加。 睾酮缺乏已被证实在男性阿尔茨海默病 (AlzD) 的风险、发病和进展中发挥着重要作用。 AlzD 发病前的干预可以在临床前阶段促进 AlzD 病理生理学，此时干预措施可能 雄激素剥夺疗法（ADT）在治疗前列腺癌和睾酮方面取得了最大的成功。 直接针对睾酮水平的年龄相关性性腺功能减退症替代疗法 (TRT) 检验这种雄激素对阿尔茨海默病（其前驱症状）的风险影响的宝贵机会 在拟议的研究中，我们将研究轻度认知障碍（MCI）和共病健康状况。 利用百万退伍军人计划 (MVP) 的遗传和临床数据来确定低水平的影响 睾酮、ADT 和 TRT 对 MCI 和 AlzD 的相对风险我们勇敢地面对长期影响。 低睾酮、ADT 和 TRT 的影响将受到 AlzD 多基因风险和雄激素变化的调节 这些遗传因素代表了疾病易感性和预先存在的关键标记。 激素敏感性尚未纳入保护性和有益作用的研究中 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 co- 的风险。 MVP 人群中睾酮水平较低会增加导致痴呆的疾病。 接下来，我们将确定睾酮水平的临床操作是否与风险差异相关 对于 MCI 和 AlzD，我们承认接受 ADT 的人患 MCI 和 AlzD 的风险会增加。 以及与有前列腺癌病史但未接受过前列腺癌治疗的男性相关的共病健康状况 我们进一步发现接受 TRT 治疗的男性患这些疾病的风险会降低。 与未接受激素替代治疗的睾酮水平低的男性相关的情况我们会。 下一项测试是否预先存在的阿尔茨海默病遗传风险会改变以睾酮为中心的治疗对患者的影响 我们观察到 ADT 和 TRT 对认知和健康的影响。 对于阿尔茨海默病遗传风险较高的个体来说，结果会更好。最后，我们将确定是否会出现这种情况。 由于 CAG 重复长度或配体和 DNA 结合域导致雄激素敏感性发生遗传驱动的变化 突变调节 ADT 和 TRT 的长期风险和益处。 AR 基因的变异将在 ADT 后增加 MCI 和 AlzD 的风险。 更多雄激素敏感个体将从 TRT 中受益更多，因此表现出降低的风险 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，获得了 MVP。 代表了探索以睾酮为中心的治疗对痴呆症影响的理想资源 风险，并通过评估长期研究提供遗传信息精准医学的原理验证模型。 在遗传信息设计的背景下，ADT 和 TRT 对认知健康的术语风险和益处， 拟议的研究将为睾酮作为 MCI 和 AlzD 风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有反应的阿尔茨海默病相关关键通路的理解。 本研究还将阐明与 ADT 和 TRT 相关的长期风险和益处，并阐明 这些在某些情况下有效的治疗是否会启动或延迟病理生理学 最后，我们将确定我们的假设是否成立。 驱动的、遗传信息研究调查潜在的遗传风险（即阿尔茨海默病的多基因风险）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 我们相信我们的研究非常适合 TRT 的使用和减少 ADT 的痛苦结果。 MVP，并将展示更广泛的生物医学研究计划的有效性和 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