中华预防医学杂志    2017年09期 青春期下丘脑-垂体-肾上腺轴发育模式及其在情绪障碍中的意义    PDF     文章点击量:267    
中华预防医学杂志2017年09期
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文章信息

段晓楠 孙莹
DuanXiaonan,SunYing
青春期下丘脑-垂体-肾上腺轴发育模式及其在情绪障碍中的意义
Developmental pattern of hypothalamic-pituitary-adrenal axis during pubertal transition and implications for emotional disorders
中华预防医学杂志, 2017,51(9)
http://dx.doi.org/10.3760/cma.j.issn.0253-9624.2017.09.019

文章历史

投稿日期: 2017-04-16
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青春期下丘脑-垂体-肾上腺轴发育模式及其在情绪障碍中的意义
段晓楠 孙莹     
段晓楠 230032 合肥,安徽医科大学公共卫生学院儿少卫生与妇幼保健学系人口健康与优生安徽省重点实验室
孙莹 230032 合肥,安徽医科大学公共卫生学院儿少卫生与妇幼保健学系人口健康与优生安徽省重点实验室
摘要: 青春期在个体生命历程中不仅是体格发育的重要时段,也是神经内分泌变化的关键期。下丘脑-垂体-肾上腺(HPA)轴作为重要的神经内分泌轴,其在青春期的功能变化及对身心健康和情绪症状的影响越来越值得关注,然而目前对其发育模式与昼夜节律变化的了解知之甚少。近期研究提示HPA轴在青春期的特定发育模式与青少年情绪障碍风险密切相关,这一紧密联系使得识别静息与应激状态下HPA功能发育轨迹,评价HPA轴特定发育表型对青春期情绪症状及情绪障碍的预测效应成为研究热点,一般使用皮质醇昼夜节律和皮质醇觉醒应答评价HPA轴功能。在青春期启动至随后的发育进程中,阐明HPA轴在各阶段的功能模式变化,对早期筛查、干预与治疗青少年情绪障碍有重要的指导意义。
关键词 :青春期;下丘脑-垂体系统;氢化可的松;情绪障碍
Developmental pattern of hypothalamic-pituitary-adrenal axis during pubertal transition and implications for emotional disorders
DuanXiaonan,SunYing     
Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University; Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei 230032, China
Corresponding author: Sun Ying, Email: sy54@yeah.net
Abstract:During an individual's life, puberty is not only a crucial phase for physical development, but a key period for neuroendocrine transformation. As a major neuroendocrine axis, the influence of hypothalamic-pituitary-adrenal (HPA) axis's changes during puberty on mental and physical health, as well as emotional symptoms, is causing a growing attention. However, information of its developing pattern and circadian variation is limited. Recent research has demonstrated that certain developing pattern of HPA axis in puberty is closely related to the adolescent emotional disorders, which highlights the recognition of HPA functions developing paths under both resting and stress state and the evaluation of its prediction effect for the adolescent emotional disorders. Generally, cortisol awakening response is utilised to assess HPA functions. Elaborating the variation of HPA axis functions from the puberty to the later developing process provides much guiding significance for the early screening, intervention and treatment of adolescent emotional disorders.
Key words :Puberty;Hypothalamo-hypophyseal system;Hydrocortisone;Mood disorders
全文

青春期是以神经内分泌功能的重大变化为标志的一段时期,也是下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴静息功能与应激应答功能发育的关键期。在青春期情绪障碍高发的背景下,鉴于HPA轴功能异常与情绪障碍风险的密切关联,在青春期启动至随后的发育进程中,识别HPA轴静息与应激状态下的功能发育轨迹,评价HPA轴特定发育表型对青春期情绪症状及情绪障碍的预测效应,是对当前发育精神病理学倡导的"通过生物学标志物预测精神疾病的易感性"的积极呼应,也为青少年情绪障碍的早期干预与治疗指导提供了新思路。

一、青春期情绪障碍与HPA轴的功能评估  情绪障碍是最常见的精神障碍,已成为当今全世界及我国第二大疾病负担,将成为2030年全球首位疾病负担[1,2]。情绪障碍首次发病多发生于青春期,终身的情绪障碍有25%发生在18岁前,50%发生在30岁之前[3];首发于青春期的情绪障碍,在生命历程中病程较长、成年期再次发作的风险增加4倍[4]。情绪症状在童年期没有性别差异,但在青春期结束时,女性情绪障碍的发病率约为男性的2倍[5,6,7]。从预防和公共卫生政策的角度来看,研究青春期精神病理学是重中之重。
        目前研究常用皮质醇昼夜节律和皮质醇觉醒应答(cortisol awakening response,CAR)评价静息下HPA轴功能:皮质醇昼夜节律是指个体一天中的皮质醇水平在觉醒后30~40 min增加到峰值,随后缓慢下降,在睡前达到最低点;作为皮质醇昼夜节律的一部分,CAR即清晨觉醒后最初30~45 min后皮质醇分泌增加的量。皮质醇作为HPA轴的终端产物直接反映HPA轴活动,通过测量皮质醇实现对HPA轴功能的评估[8,9,10]。皮质醇昼夜节律的评估包括对基线皮质醇水平、CAR、睡前皮质醇水平、皮质醇昼间变化斜率等。CAR常使用曲线下面积(area under curve ground, AUCg)和曲线下增加的面积(area under curve increased, AUCi)评估[11]。稳健的HPA轴活动由儿童青少年标准化心理社会应激任务引发,包含不可控和社会评价威胁两个因素,反映急性应激条件下的HPA轴活动变化。

二、HPA轴功能的发育性变化  HPA轴是人类重要的应激内分泌轴,在人类生命历程的不同阶段有着不同的生理应答模式。胎儿期HPA轴开始对外界信号有所应答,并依据胎儿环境初步塑造自身的调节节律。婴儿期由于糖皮质激素受体和HPA轴反馈调节的逐渐成熟,出生后的最初几个月内HPA轴反应性逐渐降低,对日常生活中轻微刺激的应答逐渐减少[12]。青春期是HPA轴发育重要的发展里程碑和敏感期,这一时期HPA轴对应激的高反应性可能是青春期精神病理症状高发的潜在重要生物学机制之一。成年期的HPA轴发育成熟,但对应激反应存在性别差异。
        啮齿动物中存在应激应答不足,即刚出生时静息态皮质醇水平较低,出生后2周内应激仅使皮质醇水平小幅升高。学者推论人类也存在类似的HPA轴应答不足的阶段,有证据显示这种应激应答阻滞效应始于婴儿期[13],持续至青春期前。青春期结束时,个体表现出成人样皮质醇应答模式。
        青春期启动伴随着神经内分泌功能的急剧转变,调节HPA轴的边缘系统和前额叶在青春期发育过程中经历显著的发育重塑,这个时期内HPA轴功能的发育性变化,或许有助于青少年适应发育转型带来的巨大变动。Colich等[14]发现不同青春期阶段的女生,HPA轴预测情绪障碍的应答反应不同:在青春期早期(Tanner分期<Ⅱ期),皮质醇应答的低敏性可预测重症抑郁,而在青春期后期(Tanner分期:Ⅲ~Ⅳ期),皮质醇应答的高敏性预测重症抑郁;相同应激水平下,青春期个体皮质醇应答显著高于儿童[15,16,17]。现有的大多数研究多依赖单时点的静息HPA轴功能指标,少见复合性指标和应激状态下HPA轴功能指标,造成当前对HPA轴功能的理解互相矛盾:对于昼夜节律,Shirtcliff等[18]认为昼夜节律存在扁平化趋势,而Adam[19]发现昼间斜率随年龄增加变得更加"陡峭"。而关于CAR,有研究认为清晨觉醒皮质醇水平、CAR呈发育性升高的趋势[20,21],但也有研究提示CAR随年龄增长而降低[19]或无显著年龄变化[22]。McGinnis等[23]在对童年早期儿童的横断面研究发现,当控制外化症状后,CAR与内化症状的联系随着年龄的增长而消失。为进一步理解并验证HPA轴在青春发育期的功能变化,在未来的研究中应采用多时点,多指标综合反映个体情况。

三、HPA轴功能与青少年情绪障碍的关联  青少年研究线索目前支持HPA轴功能与情绪障碍存在关联,但因HPA轴功能指标、研究设计、研究对象、情绪障碍维度等差异,尚未得出确切结论[24,25]

(一)CAR  多数研究认为情绪障碍的首发和复发与CAR升高密切相关。Adam等[26]对230名16~18岁青少年开展1年随访研究,发现高水平的基线CAR预测重症抑郁(major depressive disorder,MDD)发生风险增加。荷兰青少年生活追踪研究(Tracking Adolescents Individual Lives Study,TRAILS)发现,1 604名10~12岁青少年中,有抑郁症状的青少年CAR较高[27]。该项研究还发现基线较高的CAR可预测社会焦虑障碍(social anxiety disorders,SAD)[28]。清晨觉醒后皮质醇水平的迅速升高,表现为CAR增高,可能影响抑郁与焦虑障碍密切相关的脑区(边缘系统),干扰边缘系统内低亲和力的糖皮质激素的受体,从而增加了情绪障碍发生发展风险[26,29]
        但也有一些研究表明情绪症状与CAR减弱有关,认为低CAR是预测内化症状的新发危险因素[28,30]。Nederhof等[31]发现较低的CAR可预测青少年3年后情绪障碍的首发。McGinnis等[23]在控制儿童外化症状和年龄后,发现在22~96月龄高风险儿童中,内化症状与CAR存在负相关,即内化症状越严重,CAR减弱越显著。同样,Dietrich等[27]也发现,男童中CAR减弱与攻击行为有联系,说明与外化行为相关的皮质醇变化预示了情绪症状维度与HPA轴变化的潜在联系。
        上述关于CAR与情绪障碍关联的研究间存在争议的可能原因有:首先,研究对象与研究方法存在较大的差异,如年龄、性别、应激性经历、皮质醇测量时的情绪状态等。其次,CAR测量方法的差异,如测量时点与地点、受试者的依从性等;第三,未充分考虑遗传与环境因素,包括心理与社会环境,如有无精神或情绪障碍的家族史、有无不良情绪体验、情绪障碍病史等。

(二)皮质醇昼夜节律  青少年情绪障碍与皮质醇昼夜节律的关联性研究相对较少。在健康青少年中,皮质醇浓度日间波动较大,但波动模式较为稳定。Laceulle等[32]提出昼间HPA轴活性可视为个体一种"特质样符号"。
        大量证据显示成年抑郁症患者存在皮质醇分泌亢进与负反馈调节减弱。对17项青少年人群研究的系统综述发现,患抑郁障碍的青少年也存在昼间皮质醇分泌亢进的现象[33]。非临床样本的青少年研究也支持内化症状与昼间皮质醇浓度升高和昼夜节律扁平模式相关[34,35,36]
        焦虑障碍与皮质醇昼间节律的关联结果尚不明确。创伤后应激障碍儿童青少年的昼间皮质醇浓度增加[37],与成年人中的研究结果相反。但也有研究报告称恐慌发作青少年与对照相比,皮质醇昼夜节律差异无统计学意义[16]。由于抑郁症状至少有30%合并有焦虑症状,因此,深入阐明焦虑障碍与皮质醇的关联至关重要。
        Doane等[38]发现昼间皮质醇节律与当前及过往情绪障碍均密切相关。自我报告有悲伤与孤独感体验的青少年昼夜节律较为扁平;总体情绪不良与日间皮质醇下降速度缓慢相关,这一关联不仅在有情绪障碍的临床群体中存在,在一般人群中也同样存在。有观点认为,情绪障碍青少年表现出的日间皮质醇下降速度缓慢(扁平的斜率)代表着一种"生物学创伤",来源于过往不良应激的暴露。因此未来研究需要更多的关注既往不良经历的严重程度、发生时点和持续时间,可能均会干扰情绪障碍/情绪症状青少年皮质醇昼夜节律模式。

(三)社会应激下HPA轴应答  Caspi等[30]认为社会应激后皮质醇复原水平不能推论单一类型的情绪障碍,提示皮质醇复原可能是更为宽泛的情绪障碍的风险指标,而不是特定情绪障碍的危险因素[31]。较为缓慢的皮质醇复原模式可预测情绪障碍的新发,共患抑郁与焦虑的儿童中HPA轴应激应答呈钝化现象[39]。动物实验结果发现应激后皮质醇快速复原(即较陡峭的斜率)提示自我感知对应激的可控性和可预测性[40],因此,皮质醇应激后复原较慢提示个体对应激的可控性和可预测性较低,从而增加情绪障碍的风险。但也有部分研究发现抑郁患者相比于正常对照青少年,应激后高皮质醇水平持续时间过长[41],该机制尚不明确,需要更多研究确证这一现象是基于遗传、环境或是基因-环境的交互效应。
        情绪障碍患者中常见HPA轴应激应答呈中等程度激活,而在重度、病程较长的患者中应激应答呈现钝化,部分学者认为HPA轴应激应答功能的改变可能是情绪障碍的结局,而非预测指标。如TRAILS研究发现短暂抑郁症状史的青少年(持续时间少于2.5年)社会应激皮质醇应答增加,而抑郁症状持续时间较长(≥5年)的青少年呈钝化模式[42]。另被诊断为严重的"过度训练综合征"的运动员,其症状与情绪障碍类似,表现为训练后HPA轴应答钝化,而症状较轻的运动员则表现为相反的模式——应答增强[43]
        越来越多的学者在关注情绪障碍与HPA轴应激应答模式的同时,开始探索这一关联的可能影响因素。Mazurka等[44]报告了应激性生活事件(stressful life events,SLE)对首发和复发抑郁症青少年皮质醇应答中的可能影响,在有SLE组中,首发抑郁青少年与无抑郁青少年相比,皮质醇应答斜率较扁平,复发抑郁青少年与首发抑郁、无抑郁青少年相比,皮质醇应答复原斜率更陡峭;但在无SLE青少年中未发现首发抑郁与复发抑郁青少年皮质醇应答模式的差异。Lenaert等[45]观察了90名面临考试应激的青少年皮质醇应答模式,利用情绪注意控制量表(Emotional Attentional Control Scale,eACS)评价注意控制能力,分别对考试应激前后的唾液皮质醇水平进行评价。结果发现,考试应激前情绪注意控制能力较低可预测更多的皮质醇分泌,考试应激结束后皮质醇浓度缓慢下降,说明难以控制注意力的青少年在持续的应激暴露中,HPA轴表现出慢性的功能亢进,为识别高危青少年提供了很好的思路。一项关于情绪障碍与应激下皮质醇应答模式的Meta分析认为,现患MDD或焦虑障碍的女性在急性应激下表现出钝化的皮质醇应答反应,而现患MDD或SAD的男性则显示出皮质醇应答升高[46]。这一结果提示精神障碍与应激下皮质醇应答模式的关联存在性别差异,对于理解精神障碍中皮质醇应激应答的改变至关重要。

四、结论  上述青少年研究线索均立足于"特定时点"横断面的HPA轴单一功能指标与情绪症状/障碍的关联。目前关于HPA轴与情绪障碍的研究中,有的论证了童年早期CAR与内化症状间的消极联系,描述了在评价HPA与内化症状的联系时,考虑外化症状的共患与发育阶段的重要性[22];有的指出性别、情绪症状水平等其他因素对深入了解精神障碍中皮质醇应激反应的变化有关键影响[47]。在应激生理反应中,明确个体差异将有助于阐明生理应激与青春期早期的社会心理应激中共存的保护性和危险性因素。青春发育期皮质醇水平变化的分化性[48],表明HPA轴功能变化可能是机体适应风险的标志物,这一猜想需要在未来研究中进行验证。
        情绪障碍相关的HPA轴功能紊乱的表型为准确诊断和更有效的治疗方法提供了可能。未来研究中,HPA轴功能评价方法的标准化将为探索不同的个体差异、人口学、家庭结构和治疗干预提供机遇,也使检测和量化生命过程中的HPA轴反应模式成为可能,而建立依从性的客观评价标准,将有助于提高研究的准确性,有利于做出更加精确的预测解释。个体差异特征和皮质醇应答模式中呈现出明确的分化与联系,提示了慢性应激促进情绪性降低。受遗传基因表达或早期不良经历而产生适应性障碍的青少年,可能会产生非典型的应激应答,在青春期易遭受社会心理困难,这些研究结论为今后在青少年中进行更及时有效的干预提供了理论依据和具体方向。

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