Androgen effect on motor/cognitive outcome in Klinefelter syndrome

雄激素对克兰费尔特综合征运动/认知结果的影响

• 批准号: 7091026
• 负责人: Judith L Ross
• 金额: $ 57.5万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091026
• 关键词: androgens; clinical research; phenotype; placebos; syndrome

DESCRIPTION (provided by applicant): Klinefelter syndrome (KS), a genetic disorder that occurs in 1/1000 males, is defined by the abnormal chromosome karyotype 47.XXY (extra X chromosome), and has characteristic physical and cognitive phenotypes evident in childhood. The KS physical phenotype includes testicular failure (androgen deficiency) and tall stature. The KS neurocognitive phenotype includes diminished motor function and language-based learning difficulties. The KS behavioral phenotype involves poor self-image and shyness. The neurodevelopmental deficits associated with KS likely reflect the influence of both androgen deficiency and genetic factors on development and represent a major impediment for living a normal life with KS. It is the goal of this clinical trial to determine whether this burden can be reduced by treatment early in childhood with androgen replacement. Androgen replacement is standard in adolescent and adult KS males but has not been used in younger, prepubertal KS boys. The Phase I study will establish that the androgen oxandrolone, an FDA-approved medication for children, is also safe in prepubertal KS boys. The Phase II study is the randomized clinical trial, in which we plan to study the effects of childhood androgen replacement on motor and cognitive aspects of the KS phenotype that may result from childhood androgen deficiency. This randomized, placebo-controlled study tests a novel intervention in this population: low-dose androgen (oxandrolone) treatment for two years in KS boys (n=120), ages of 4-12 years. We predict that KS boys treated with androgen for 24 months will have improved muscle strength, compared to the placebo-treated KS boys. Second, we predict that KS boys treated with androgen for 24 months will have improved aspects of motor function including response speed, simple repetitive movement, and complex nonrepetitive motor action, compared to the placebo-treated KS boys. Third, we predict that KS boys treated with androgen (oxandrolone) for 24 months will have improved aspects of language, including verbal memory and verbal fluency and fourth, we predict that KS boys treated with androgen for 24 months will have improved aspects of simple and complex attention, compared to the placebo-treated KS boys. RELEVANCE OF THIS RESEARCH: KS is well suited for interventional studies because testicular failure is nearly universal in this disorder. Early androgen replacement is a reasonable, appropriate, and safe research treatment option in this androgen-deficient population. Therapeutic interventions for this relatively common disorder have not been forthcoming, and this proposal represents a unique opportunity to replace a missing hormone and potentially improve motor function and cognition. If successful, androgen replacement in the clinical management of KS would commence early in childhood rather than adolescence or adulthood.

描述（由申请人提供）：KlineFelter综合征（KS）是一种遗传疾病，发生在1/1000名男性中，由异常的染色体核型核型47.xxy（Extraim X Collomosom）定义，并且具有特征性的物理和认知表型。 KS物理表型包括睾丸衰竭（雄激素缺乏）和高地位。 KS神经认知表型包括运动功能减少和基于语言的学习困难。 KS行为表型涉及自我形象和害羞的差。与KS相关的神经发育缺陷可能反映了雄激素缺乏症和遗传因素对发育的影响，并代表了与KS正常生活的主要障碍。这项临床试验的目的是确定通过雄激素替代的儿童早期治疗可以减轻这种负担。雄激素替代是青春期和成年KS男性的标准配置，但尚未用于年轻的Prefubertal KS男孩。第一阶段的研究将确定，在青春期前KS男孩中，雄激素氧和儿童的药物也是安全的。 II期研究是一项随机临床试验，我们计划研究儿童雄激素替代对KS表型的运动和认知方面的影响，这可能是儿童期雄激素缺乏症。这项随机的安慰剂对照研究测试了该人群中的一种新干预：低剂量雄激素（Oxandrolone）治疗KS男孩（n = 120），年龄为4-12岁。我们预测，与安慰剂治疗的KS男孩相比，接受雄激素治疗的KS男孩将有24个月的肌肉力量提高。其次，我们预测，与安慰剂处理的KS男孩相比，接受雄激素治疗的KS男孩将有24个月的24个月的改善方面的运动功能，包括响应速度，简单的重复运动和复杂的非重复运动动作。第三，我们预测，接受雄激素（Oxandrolone）处理24个月的KS男孩将改善语言方面，包括口头记忆和口头流利性，第四个月，我们预测，与经过安慰剂训练的KS男孩相比，用雄激素治疗24个月的KS男孩将改善简单和复杂的关注方面。这项研究的相关性：KS非常适合介入研究，因为睾丸衰竭在该疾病中几乎是普遍的。在这个缺陷型雄激素人群中，早期雄激素替代是一种合理，适当且安全的研究治疗选择。对这种相对常见疾病的治疗干预措施尚未到来，该提案代表了替代缺失激素并有可能改善运动功能和认知的独特机会。如果成功，则在KS的临床管理中替代雄激素将在儿童时期开始，而不是青春期或成年。