Androgen Effects On Cognition In Turner Syndrome

描述（由申请人提供）：雄激素是影响人类和动物大脑发育和行为的激素。认知和行为的变化发生在青春期，与性激素（雌激素和雄激素）水平的显着增加，在女性和男性。激素变化在模拟成人大脑成熟的最后阶段中起着重要作用。患有特纳综合征（TS）的女孩缺失第二条X染色体的全部或部分，出生时具有发育不良的卵巢，因此在青春期之前，期间和之后缺乏卵巢雌激素和雄激素。TS代表了一种独特的，性别差异缺乏的模型，在其中研究雄激素治疗对女性认知和行为的生物学效应。正在进行的研究（NS 32531）使用1）两个TS组（开始时年龄为10-14岁）治疗4年：（a）雄激素治疗组和（B）无雄激素（安慰剂）治疗组，以及2）年龄匹配的正常女性对照组，也随访4年。此外，所有TS女孩（两个治疗组）在研究的第3年和第4年接受标准雌激素替代治疗。我们建议继续并完成这项随机、双盲临床试验。当前研究的扩展标志着一个前所未有的机会，可以纵向监测四年雄激素治疗对青春期关键时期的影响。我们收集的数据表明，治疗的效果可能与组织因素有关，导致在很长一段时间内发生变化。目前尚不清楚观察到的增量变化是继续还是平稳。延长研究时间（4年），使每个儿童完成4年治疗，将有助于确定这一点。 本项目的具体目的是：1）检查4年雄激素治疗对生长激素治疗的TS女孩的认知和心理调节的影响，2）记录青春期TS女孩（接受或未接受雄激素治疗）与年龄和VIQ匹配的正常女孩在认知和行为功能方面的差异和相似性，也进行了4年的纵向随访。具体而言，我们假设：（1）与未接受雄激素治疗的TS女孩相比，接受雄激素治疗的TS女孩在涉及手部的精细运动速度测试中表现更好，（2）与未接受雄激素治疗的TS女孩相比，接受雄激素治疗的TS女孩在某些空间感知测试中表现更快，涉及心理转变，（3）TS女孩，与未用雄激素治疗的患有TS的女孩相比，用雄激素治疗的患有TS的女孩在算术成绩测试（学术结果）上表现更好。（4）与未用雄激素治疗的患有TS的女孩相比，用雄激素治疗的患有TS的女孩在语言、执行功能和注意力测试上表现相似，（5）雄激素治疗的TS受试者和对照者在空间知觉处理时间和算术学业成绩测试中的认知差异将随着时间的推移而减少但不会消失，这表明TS中的某些认知缺陷只是部分可逆的，（6）雄激素处理的TS受试者和对照者在手部精细运动速度测试中的表现差异将随着时间的推移而减少并消失，这表明TS中的某些认知缺陷是可逆的。 这项对青少年认知和社会发展的持续研究是理解正常大脑发育的重要一步。此外，这些数据将有助于确定如何优化特纳综合征的认知功能，并将扩展男性/女性认知二型性机制的知识。

DESCRIPTION (provided by applicant): Androgens are hormones that influence brain development and behavior in humans and animals. Cognitive and behavioral changes occur during puberty, in concert with marked increases in sex hormone (estrogen and androgen) levels in females and males. Hormonal changes play a significant role in modeling the final stages of maturation in the adult brain. Girls with Turner syndrome (TS) are missing all or part of the second X chromosome, are born with dysgenetic ovaries, and therefore lack ovarian estrogen and androgen before, during, and after puberty. TS represents a unique, sex hormone-deficient model in which to study the biological effects of androgen treatment on cognition and behavior in females. The ongoing study (NS32531) utilizes 1) two TS groups (ages 10-14 years at start) treated for four years: (a) androgen-treated and (b) no androgen (placebo)-treated and 2) an age-matched, normal female control group, also followed for four years. Additionally, all TS girls (both treatment groups) receive standard estrogen replacement therapy during the 3rd and 4th years of the study. We propose to continue and complete this randomized, double-blind clinical trial. Extension of the current study marks an unprecedented opportunity to monitor longitudinally the influence of four years of androgen treatment across a critical period of adolescence. The data we have collected suggest that the effects of treatment may be related to organizational factors, resulting in changes that evolve over an extended period of time. It is unclear at present whether observed incremental changes continue or plateau. The extension (four years) of the study to permit each child to complete the four years of treatment will help to determine this. The specific aims of this project are to: 1) examine the effects of 4 years of androgen treatment on cognition and psychological adjustment in growth hormone-treated TS girls, 2) document the differences and similarities in cognitive and behavioral function between adolescent TS girls (treated or not treated with androgen) and age- and VIQ-matched normal girls, also followed longitudinally for 4 years. Specifically, we hypothesize that: (1) Girls with TS, treated with androgen, will perform better on tests of fine motor speed involving the hand, compared to girls with TS not treated with androgen, (2) Girls with TS, treated with androgen, will perform faster on certain tests of spatial perception, involving mental transformation, compared to girls with TS not treated with androgen, (3) Girls with TS, treated with androgen, will perform better on tests of arithmetic achievement, an academic outcome, compared to girls with TS not treated with androgen, (4) Girls with TS, treated with androgen, will perform similarly on tests of language, executive function, and attention, compared to girls with TS not treated with androgen, (5) The cognitive differences between androgen-treated TS subjects and controls on tests of spatial perceptual processing time and arithmetic academic performance will diminish but not disappear over time, indicating that certain cognitive deficiencies in TS are only partially reversible, and (6) The performance differences between androgen-treated TS subjects and controls on tests of fine motor speed of the hand will diminish over time and disappear, indicating that certain cognitive deficiencies in TS are reversible. This proposed continuing investigation of adolescent cognitive and social development represents an important step in understanding normal brain development. In addition, these data will help determine how to optimize cognitive function in Turner syndrome and will extend knowledge of the mechanisms of male/female cognitive dimorphisms.