1. 皮质醇的生理功能与调控机制
1.1 皮质醇的基础生物学特性
皮质醇，作为一种由肾上腺皮质分泌的糖皮质激素，是人体内重要的应激激素，在维持生理稳态中扮演着核心角色 1。其分泌受下丘脑-垂体-肾上腺轴（HPA轴）的精确调控。HPA轴的激活始于下丘脑分泌促肾上腺皮质激素释放激素（CRH），CRH进而刺激垂体前叶释放促肾上腺皮质激素（ACTH），最终促使肾上腺皮质分泌皮质醇 23。这一复杂的轴线通过正负反馈机制进行调节，确保皮质醇水平维持在生理范围内，以应对内外环境的挑战 4。
皮质醇的分泌呈现显著的昼夜节律性，通常在清晨醒来前达到峰值，随后在一天中逐渐下降，至夜间达到最低水平 1。这种节律性分泌模式对于个体适应日常活动和睡眠周期至关重要 56。除了昼夜节律，皮质醇还以脉冲形式释放，这种超昼夜节律的脉冲波动在血液和靶组织中也发挥着重要作用 6。
皮质醇的生理功能广泛而多样。在能量代谢方面，皮质醇能够促进糖异生，增加肝脏葡萄糖输出，抑制外周组织对葡萄糖的摄取（如脂肪细胞和骨骼肌），同时促进脂肪分解，为机体提供应对压力的能量储备 78910。在免疫调节方面，皮质醇表现出强大的抗炎和免疫抑制作用，能够调节细胞因子（如IL-6、IL-1β和TNF-α）的产生，从而在应激状态下帮助机体避免过度炎症反应造成的损害 111213。此外，皮质醇在应激反应中居于核心地位，通过影响神经认知功能，如促进恐惧记忆的巩固，来帮助个体为未来的威胁做好准备 1114。急性应激下，皮质醇水平迅速升高，有助于机体调动资源，启动“战斗或逃跑”反应；然而，长期或慢性的应激暴露会导致皮质醇调节失衡，进而产生一系列适应不良的生理和心理后果，包括代谢综合征、肥胖、心血管疾病及精神健康问题等 115。
1.2 皮质醇水平的影响因素
皮质醇的分泌水平受到多种生理和环境因素的动态调节，这些因素共同决定了HPA轴的激活程度及皮质醇的最终输出。其中，压力类型、睡眠质量、运动强度及饮食是影响皮质醇水平的关键因素。
压力类型 对皮质醇分泌具有显著影响。急性压力通常会导致皮质醇水平迅速且短暂的升高，以帮助机体应对即时威胁，例如“战斗或逃跑”反应 111。这种急性升高是适应性的，有利于短期内的生存和表现 1。然而，长期或慢性压力则可能导致皮质醇调节失衡。在慢性应激初期，皮质醇水平可能持续升高，以应对持续的挑战。但如果长期炎症性应激发生，ACTH水平可能恢复到接近基础水平，而皮质醇水平仍保持升高，这部分是由于肾上腺敏感性增加或皮质醇代谢下降所致 1。长期的皮质醇高水平暴露可能产生负面影响，包括诱发胰岛素抵抗、影响免疫功能以及导致一系列慢性疾病 19。
睡眠质量 与皮质醇节律之间存在着双向的紧密关联。正常的睡眠模式有助于维持皮质醇的昼夜节律，即清晨达到峰值，夜间降低 1。睡眠剥夺或不良睡眠质量则会显著扰乱这一节律，导致HPA轴活动增加，从而引起皮质醇水平升高 1617。例如，部分睡眠限制通常会导致有害的生理反应，而长期完全睡眠不足甚至可能导致死亡 16。研究表明，改善睡眠质量，如通过镁补充剂干预，可以显著降低老年人的血清皮质醇浓度，并改善睡眠效率和睡眠时间 18。此外，孤独的个体报告睡眠质量较差 19，这可能间接影响皮质醇调节。
运动强度 也是调节皮质醇水平的重要因素。适度的运动可以作为一种健康的应激源，短期内引起皮质醇的升高，一项研究发现，高强度（心率储备的70%）的30分钟运动能有效抑制随后心理社会应激（如Trier社会应激测试）引起的唾液皮质醇反应，表现为总皮质醇水平较低，反应减弱，并更快恢复到基线水平 20。这表明运动引起的HPA轴反应与随后应激任务的皮质醇反应呈负相关，提示剧烈运动释放的皮质醇可能抑制了后续应激反应 20。长期而言，规律的运动有助于改善HPA轴的应激反应性，使其对随后的心理社会应激源反应减弱 21。一项系统综述和Meta分析也证实，体育活动能够有效降低皮质醇水平，并改善睡眠质量 21。
饮食 对皮质醇分泌同样具有调节作用。例如，生酮饮食（低碳水化合物饮食）可能对皮质醇水平产生影响。一项系统综述和Meta分析指出，短期（<3周）低碳水化合物饮食会适度增加静息皮质醇水平，而长期（≥3周）则无显著影响 22。此外，长时间运动后，低碳水化合物饮食会导致运动后皮质醇水平显著升高 22。相反，地中海饮食干预则被发现可以显著降低孕妇的感知压力和焦虑，并改善睡眠质量，同时提高皮质醇/可的松比率，这可能反映了皮质醇代谢的积极变化 23。此外，膳食镁补充剂已被证明可以改善老年人的睡眠质量，并显著降低血清皮质醇浓度 18。这些研究强调了饮食在皮质醇调控中的潜在作用。
2. 皮质醇异常与慢性疲劳的病理关联
2.1 慢性疲劳综合征（CFS）中的皮质醇特征
慢性疲劳综合征（Chronic Fatigue Syndrome, CFS），又称肌痛性脑脊髓炎（Myalgic Encephalomyelitis, ME），是一种以持续性、无法解释的严重疲劳为核心症状，并伴有认知障碍、睡眠障碍、肌肉关节疼痛等多种非特异性症状的复杂疾病。在CFS患者中，皮质醇水平的异常是其病理生理学特征之一，尤其表现在HPA轴功能的紊乱上。
大量研究表明，CFS患者常表现出低皮质醇血症（hypocortisolism），即皮质醇分泌水平低于正常人。这种低皮质醇状态并非绝对，但在一部分CFS患者中普遍存在。多项研究发现，CFS患者的基线皮质醇水平（包括血浆、唾液和尿液样本）通常偏低 242526。例如，一项针对121名CFS患者和64名对照组的24小时尿液游离皮质醇（urinary free cortisol）测量研究显示，CFS患者的尿液游离皮质醇水平显著低于对照组，且这种降低与是否伴有精神疾病、用药、睡眠障碍或残疾程度无关 26。另一项Meta分析也指出，与健康对照组相比，CFS患者的基线皮质醇水平显著降低 27。尽管如此，关于CFS患者皮质醇水平的报告存在异质性，一些研究发现基线皮质醇水平正常，这可能与研究方法学差异、患者选择标准、疾病阶段以及皮质醇测量方式（如短期日分泌量与长期蓄积量）有关 242829。然而，对多项研究进行整合分析后，仍有证据支持CFS患者存在轻度低皮质醇血症 25。
除了基线水平的降低，CFS患者的皮质醇昼夜节律也常表现出紊乱。正常的皮质醇节律是在清晨达到高峰，随后逐渐下降，夜间最低。然而，CFS患者可能出现清晨皮质醇峰值钝化、日间下降不足或夜间皮质醇水平相对较高的情况，从而导致整体昼夜节律的扁平化或异常 2528。这种昼夜节律的紊乱可能进一步加剧患者的疲劳感和睡眠障碍。例如，一项研究利用毛发和唾液样本测量皮质醇发现，CFS患者的唾液皮质醇日分泌总量（反映短期日分泌）显著低于健康对照组，但毛发皮质醇浓度（反映过去三个月的长期平均水平）与对照组无显著差异，这可能提示CFS患者皮质醇节律的改变而非长期总分泌量的显著降低 28。
更关键的皮质醇特征在于HPA轴的负反馈增强（enhanced negative feedback）和应对挑战反应迟钝（blunted responses to challenge）。这意味着即使皮质醇水平较低，下丘脑-垂体对皮质醇的抑制作用却异常敏感，导致HPA轴难以正常激活并提升皮质醇水平以应对应激 253031。例如，在促肾上腺皮质激素释放激素（CRH）或胰岛素诱导的低血糖刺激试验中，CFS患者的ACTH和皮质醇反应往往弱于健康对照，这表明HPA轴的反应性受损 2531。这种增强的负反馈机制被认为是CFS患者低皮质醇状态的重要原因之一，使得HPA轴对压力信号的响应不足，从而影响机体应对压力的能力 25。
一项2023年发表的Meta分析，针对CFS患者与健康对照组的尿液生物标志物进行了系统回顾和分析，其中特别关注了尿液游离皮质醇水平。尽管该Meta分析指出在尿液游离皮质醇水平上CFS患者与健康对照组存在显著差异，但由于纳入研究的高度异质性，难以得出一致的结论 32。不过，许多研究一致认为CFS患者存在HPA轴功能障碍，表现为轻度皮质醇低下、昼夜节律异常以及HPA轴负反馈敏感性增加和应激反应迟钝 2531。这些皮质醇异常被认为与CFS的症状严重程度和功能损害密切相关 25。值得注意的是，这些HPA轴的改变可能并非CFS的初始病因，而是在疾病发展过程中受多因素（如不活动、去适应和睡眠障碍）影响而形成或加剧的 30。甚至有研究表明，童年创伤与CFS患者的神经内分泌功能障碍相关，尤其是那些有童年创伤暴露的CFS患者，其清晨唾液皮质醇浓度低于对照组 33。
2.2 皮质醇异常与CFS症状的互作机制
慢性疲劳综合征（CFS）中皮质醇水平的异常，特别是普遍存在的低皮质醇状态，并非孤立的现象，而是与CFS的核心症状，如免疫炎症、线粒体功能障碍以及神经认知功能受损，形成复杂的互作网络。这种互作机制在很大程度上解释了CFS病理生理学的复杂性。
1. 低皮质醇状态与免疫炎症：
皮质醇作为一种重要的免疫抑制剂和抗炎激素，在维持免疫稳态中发挥关键作用。当皮质醇水平长期偏低时，其对免疫系统的负向调节作用减弱，可能导致免疫激活和炎症反应的失控 3435。研究发现，CFS患者常伴有促炎细胞因子（如白细胞介素-6 [IL-6]、肿瘤坏死因子-α [TNF-α]和白细胞介素-1β [IL-1β]）水平的升高 363738。这种炎症状态的持续存在被认为是导致疲劳、疼痛和认知功能障碍的重要因素。例如，有研究指出，抑郁（CFS患者常见共病）与晚间唾液皮质醇水平和炎症标志物（IL-2, IL-6, TNF-α）升高直接相关，提示皮质醇、炎症与心理症状之间的复杂联系 36。低皮质醇症可能通过减弱对促炎细胞因子的抑制，从而加剧全身性炎症，形成一个恶性循环，进一步损害身体功能。
2. 低皮质醇状态与线粒体功能障碍：
线粒体是细胞的“能量工厂”，其功能障碍与疲劳的发生密切相关。虽然直接将低皮质醇与线粒体功能障碍联系起来的研究较少，但皮质醇在能量代谢中的关键作用提示了潜在的联系。皮质醇影响葡萄糖和脂肪酸的代谢，而线粒体是这些能量底物氧化磷酸化产生ATP的主要场所。理论上，皮质醇水平异常可能干扰正常的能量底物供应和利用，从而间接影响线粒体效率。此外，慢性炎症本身也可能导致线粒体损伤和功能下降，而低皮质醇导致的炎症加剧了这一过程 34。有研究提到，持续的炎症，伴随氧化应激和线粒体功能障碍，与CFS和纤维肌痛患者的疼痛、疲劳、记忆障碍和抑郁等症状密切相关 34。
3. 低皮质醇状态与神经认知功能：
CFS患者普遍存在“脑雾”现象，表现为注意力不集中、记忆力下降、信息处理速度变慢等认知功能障碍。皮质醇通过作用于中枢神经系统，特别是海马体和前额叶皮质，对认知功能产生重要影响。适量的皮质醇有助于认知功能的维持，但皮质醇过高或过低都可能损害认知表现。在低皮质醇状态下，神经递质的平衡可能被打破，炎症细胞因子也可能穿过血脑屏障，直接影响神经元功能，导致认知障碍的发生 34。例如，一项针对新诊断头颈癌患者的研究发现，疲劳与皮质醇昼夜节律斜率（stress biomarkers）和炎症标志物（如C反应蛋白）之间存在复杂的网络联系，提示疲劳与HPA轴和炎症之间的潜在神经认知机制 37。
4. 长新冠与皮质醇降低及疲劳的关联：
近年来，长新冠（Long COVID）作为一种新的后病毒感染综合征，其许多症状与CFS高度重叠，其中最突出的便是持续性疲劳和劳累后不适。2023年《自然》（Nature）杂志上的一项研究深入探讨了长新冠患者的免疫特征，发现与匹配的对照组相比，长新冠患者的循环髓系和淋巴细胞群存在显著差异，且针对SARS-CoV-2的体液免疫反应增强。更重要的是，该研究观察到，长新冠患者的皮质醇水平较低，并且这种皮质醇降低与患者的疲劳症状存在关联 39。虽然另一项2024年的研究未发现长新冠患者存在肾上腺功能障碍或皮质醇水平与症状的直接关联 40，但前者的发现进一步支持了皮质醇异常，特别是低皮质醇状态，可能在疲劳相关疾病（包括CFS和长新冠）的病理生理学中发挥作用。这种关联提示，皮质醇水平可能作为疲劳性疾病的一个生物标志物，并且针对HPA轴功能的干预可能成为改善疲劳症状的潜在策略。
总而言之，CFS中的低皮质醇状态被认为促成了免疫系统失调、慢性炎症的持续，并可能间接影响能量代谢和线粒体功能，同时直接或间接地损害神经认知功能。这种多系统、多层面的互作机制共同构成了CFS的复杂病理生理学基础，也为未来的诊断和治疗提供了新的视角。
3. 过劳状态下的皮质醇动态演变
3.1 过劳的阶段性皮质醇反应
过劳（burnout）作为一种由长期、过度工作压力引起的耗竭状态，其生物学基础涉及神经内分泌系统的显著改变，尤其是皮质醇动态的演变。研究表明，过劳状态下的皮质醇反应并非单一模式，而是呈现出一种阶段性的双相模式：初期表现为皮质醇水平的升高，而后随着过劳的持续和加重，可能转向皮质醇水平的降低，甚至出现肾上腺功能耗竭的特征。
过劳初期：交感神经激活与皮质醇升高
在过劳的早期阶段，个体面临持续的工作压力和高负荷，机体启动应激反应，导致交感神经系统持续激活。此时，HPA轴也随之兴奋，表现为皮质醇分泌的增加。这种初期的皮质醇升高被认为是机体对压力的适应性反应，旨在调动机体资源以应对挑战。多项研究发现，职业倦怠的早期或高压环境下，皮质醇水平呈升高趋势。例如，一项针对医生的研究显示，与对照组相比，职业倦怠组的血清和唾液皮质醇、ACTH及其他应激指标均显著升高 41。另一项研究也指出，职业倦怠与持续的自主神经系统激活和交感-肾上腺髓质轴功能障碍有关，表现为皮质醇水平的改变 42。在这种情况下，皮质醇的升高有助于维持注意力和警觉性，但长期的高水平也可能对心血管和代谢系统产生负面影响 42。
过劳后期：肾上腺功能耗竭与皮质醇降低
如果压力持续存在且得不到有效缓解，机体长期处于高负荷应激状态，可能导致HPA轴的调节能力下降，甚至出现功能性耗竭。此时，皮质醇的升高趋势可能逆转，表现为基线皮质醇水平的降低，甚至对刺激的反应性减弱。这种现象被称为“肾上腺疲劳”或“肾上腺功能不足”，尽管“肾上腺疲劳”这一概念在医学界仍存在争议，但其所描述的皮质醇分泌不足在长期慢性应激个体中确实可见 43。
多项研究支持过劳后期皮质醇水平降低的观点。一项针对急性心理社会应激下疲劳相关皮质醇反应的研究发现，在疲劳前期或未恢复的疲劳患者中，皮质醇对特里尔社会应激测试（TSST）的反应性较低，表明HPA轴的反应减弱 44。另一项针对住院医师的研究也发现，工作需求增加和皮质醇水平降低与一年后职业倦怠的发生显著相关 45。这提示，皮质醇水平的下降可能是长期过劳导致HPA轴适应不良或耗竭的表现。在严重的情况下，可能发展为临床上的肾上腺功能不全。
肾上腺功能不全的临床特征
肾上腺功能不全（Adrenal insufficiency）是指肾上腺皮质无法产生足够的皮质醇。虽然与过劳相关的“肾上腺疲劳”并非Addison氏病（原发性肾上腺功能不全）那样严重的病理状态，但长期过劳导致的皮质醇分泌不足与Addison氏病存在症状上的重叠，如慢性疲劳、乏力、情绪低落等 4346。一项临床病例报告描述了一名长期使用类固醇的患者，最终出现肾上腺功能不全的并发症，这从侧面提示了长期应激（尽管本例是外源性类固醇）对肾上腺功能的潜在影响 47。研究也指出，持续过度训练（一种特殊的过劳形式）可能导致运动员出现“过度训练综合征（Overtraining Syndrome）”，其症状包括慢性疲劳和倦怠，并被认为与肾上腺功能不全有关 43。尽管具体的机制仍在探索中，但这种从皮质醇升高到降低的双相模式，反映了HPA轴在长期应激下的动态失调和适应性极限。理解这种阶段性变化对于早期识别过劳和采取针对性干预至关重要。
3.2 职业人群的实证研究
在特定职业群体中，由于长期承受高强度的工作压力和责任，过劳现象尤为普遍。对这些职业人群进行实证研究，有助于更深入地理解长期过劳对皮质醇节律的影响及其与疲劳累积的量化关联。护士和运动员是典型的过劳高风险群体，他们的研究数据为此提供了宝贵的洞察。
护士群体：职业倦怠与皮质醇节律异常
护士因其工作性质，常面临高压力、长时间工作、轮班以及情感耗竭等挑战，使其成为职业倦怠的高发人群 48。多项研究聚焦于护士群体皮质醇水平的动态变化，以探究其与职业倦怠及疲劳的关联。
一项针对279名护士的大样本研究发现，具有职业倦怠症状（Maslach Burnout Inventory, MBI量表得分较高）的护士，其日间唾液皮质醇释放量显著高于无倦怠症状的护士 48。具体而言，满足两项职业倦怠标准的护士（情绪耗竭、去人格化、个人成就感降低等），其全天皮质醇释放量高于仅满足一项或无倦怠症状的护士 48。这表明，在职业倦怠状态下，HPA轴处于持续活跃或过度激活状态，皮质醇水平代偿性升高以应对长期压力。然而，这种高皮质醇状态并非总是持续，在某些情况下，长期的压力也可能导致皮质醇反应的钝化或降低。例如，一项在COVID-19大流行期间对医护人员进行的研究显示，与疫情前相比，护士的毛发皮质醇浓度（反映长期皮质醇水平）显著升高，尤其是在高风险环境中工作的护士 49。这进一步佐证了高压工作环境对皮质醇水平的长期累积影响。
值得注意的是，另有研究指出，在慢性压力或更严重的职业倦怠阶段，皮质醇水平可能出现下降或昼夜节律紊乱 50。这提示皮质醇动态可能存在一个从适应性升高到代偿性降低或功能耗竭的演变过程。对护士群体而言，持续的高压工作和睡眠剥夺（例如倒班工作），也可能导致皮质醇昼夜节律的改变，进而影响疲劳的恢复。例如，夜班工作者皮质醇节律可能出现紊乱，清晨皮质醇峰值延迟或幅度减小，这与疲劳感的加剧密切相关。
运动员群体：过度训练与皮质醇累积疲劳
运动员，尤其是精英运动员，为了追求卓越表现，常常进行高强度训练，这使其面临生理和心理的双重压力，并可能导致疲劳累积 51。皮质醇作为评估生理应激和训练负荷的指标，在运动员监测中扮演重要角色。
一项针对足球运动员的研究揭示了强化训练期对皮质醇水平的影响。研究发现，为期两周的强化训练导致运动员皮质醇水平显著升高，同时伴随睾酮/皮质醇比率（T/C比率）的下降以及肌酸激酶和C反应蛋白等炎症指标的上升 52。T/C比率被用作评估训练压力和恢复状态的指标之一，其下降通常预示着疲劳的累积 52。这项研究表明，高强度训练负荷导致皮质醇升高，并与神经肌肉疲劳、肌肉损伤以及合成代谢/分解代谢状态的改变相关 52。
然而，皮质醇在运动员疲劳监测中的应用并非没有挑战。例如，一项针对大学女子长曲棍球运动员的纵向研究显示，尽管训练负荷和运动员主观健康评分在整个赛季中存在显著变化，但唾液皮质醇水平并未表现出显著的周间差异，且与运动员整体健康状况和训练负荷的相关性微弱 53。这可能提示，在某些训练状态下，急性皮质醇反应的监测可能比长期基线水平更能反映运动员的即时应激状态 53。另一项针对精英篮球员的研究也发现，赛前晚间高或低升糖指数碳水化合物膳食对运动员的唾液皮质醇水平无显著影响，且皮质醇与睡眠质量之间关联不明显 54。这些结果提示，运动员的皮质醇动态可能受到多种因素的复杂影响，且其作为单一疲劳生物标志物的敏感性可能因个体、运动类型和测量方法而异。
总体而言，护士和运动员的实证研究表明，长期高压环境或高强度训练负荷均可引起皮质醇水平的动态改变。初期常表现为皮质醇升高以应对压力，但随着过劳的持续，HPA轴可能出现适应不良，导致皮质醇反应钝化或基线水平的改变，进而加剧疲劳的累积。这些发现强调了持续监测皮质醇节律，并结合其他生理和主观指标，以早期识别和干预职业人群过劳的重要性。
4. 基于皮质醇调节的过劳控制策略
鉴于皮质醇在过劳状态发生发展中的关键作用，通过调节皮质醇水平来管理和预防过劳，已成为一个重要的研究方向。针对HPA轴功能的干预策略既包括非药物手段，也涵盖了药物和技术干预。本节将详细探讨这些策略及其作用机制。
4.1 非药物干预手段
非药物干预策略因其安全性高、易于实施且副作用小而受到广泛关注。这些方法主要通过调节HPA轴活性、改善应激反应、促进身心放松等途径来影响皮质醇水平，从而缓解和预防过劳。
4.1.1 自然暴露干预
森林浴（Forest Bathing），或称“森林疗法”，是一种在日本起源的健康实践，强调通过在森林环境中沉浸式体验来改善身心健康。近年来，多项研究证实了森林浴对皮质醇水平及自主神经系统平衡的积极影响。
森林环境独特的物理和化学因子，如清新的空气、植物释放的挥发性有机化合物（如萜烯）以及自然声景，被认为能够诱导放松反应。研究表明，在森林中漫步或静坐可以显著降低唾液皮质醇水平，同时增加副交感神经活动（表现为心率变异性增加）并降低交感神经活动（表现为血压和心率下降），从而促进整体的放松和应激缓解。一项针对儿童癌症幸存者的实验研究发现，森林疗法能够显著降低唾液皮质醇水平，同时降低α-淀粉酶（另一个应激生物标志物）和免疫球蛋白A（IgA）的水平，提示其对HPA轴和免疫系统的积极调节作用 55。这些生理变化共同有助于减轻生理应激，改善情绪状态，进而对过劳状态下的高皮质醇水平提供有效干预。
4.1.2 运动与睡眠管理
运动强度 对皮质醇水平的影响具有双重性。急性高强度运动会暂时性升高皮质醇，以应对能量需求和生理应激。然而，长期规律的适度运动则有助于优化HPA轴的应激反应，使其对日常应激源的反应更为稳健。例如，一项研究指出，持续睡眠限制会使女性运动员的唾液皮质醇曲线下面积（AUC）增加42%，并显著降低其抗阻运动质量，增加感知疲劳 56。这提示，过度训练或睡眠不足导致的生理应激可能通过皮质醇的异常升高来体现。反之，控制好运动强度和训练量，避免过度训练，是维持HPA轴健康反应的关键。对于普通人群而言，规律的低至中等强度运动，如快走、瑜伽、太极等，已被证明能有效降低基础皮质醇水平，改善睡眠质量，并增强应对压力的能力。
VR呼吸生物反馈 是一种新兴的放松技术，它结合了虚拟现实（VR）技术和呼吸生物反馈原理，旨在帮助个体学习如何通过控制呼吸来调节自主神经活动。通过实时监测呼吸模式、心率变异性等生理指标，并将其可视化呈现在VR环境中，使用者可以直观地学习并掌握放松技巧。一项研究发现，仅12分钟的VR呼吸生物反馈放松训练就能显著降低唾液皮质醇浓度、心率和呼吸频率，同时改善自我报告的疲劳和紧张程度 57。这表明VR呼吸生物反馈能够有效激活副交感神经系统，抑制HPA轴的过度激活，从而降低皮质醇水平，为过劳个体提供了一种便捷且有效的应激管理工具。
4.1.3 营养补充
饮食在调节皮质醇水平和缓解过劳方面发挥着重要作用，某些特定的营养补充剂被发现具有调节HPA轴功能、抗炎或抗氧化作用。
抹茶（Matcha），一种绿茶粉末，富含茶氨酸、儿茶素和咖啡因。其中的茶氨酸被认为具有放松和抗焦虑的特性，能够通过增加大脑中的α波活动来促进放松，并可能影响神经递质的平衡。尽管直接针对抹茶对皮质醇影响的研究仍在进行中，但绿茶中的多酚类物质，如表没食子儿茶素没食子酸酯（EGCG），已被证实具有抗炎和抗氧化的作用 5859。通过减少系统性炎症，抹茶可能间接有助于维持HPA轴的健康功能，减轻因慢性炎症导致的皮质醇失调。
合生元（Synbiotics），是益生菌和益生元的混合物，旨在改善肠道菌群的组成和功能。肠道-脑轴是一个双向交流系统，肠道微生物群通过神经、内分泌和免疫途径影响宿主的生理和行为，包括HPA轴的活动。有证据表明，肠道菌群的失衡（肠道菌群失调）可能与HPA轴的过度激活和皮质醇水平的升高有关。通过补充合生元来优化肠道菌群，可以改善肠道屏障功能，减少炎症，并可能调节神经递质的产生，从而对HPA轴产生积极影响，有助于降低应激诱导的皮质醇分泌。例如，在长新冠患者中，肠道菌群失调与皮质醇水平的改变、慢性炎症和疲劳症状密切相关 60。虽然直接证明合生元对过劳者皮质醇水平的调节作用仍需更多研究，但其对肠道健康的积极影响有望间接缓解过劳相关的生理应激。
此外，大豆蛋白补充剂也被研究其对激素反应的影响。一项系统综述指出，大豆蛋白补充剂对睾酮和皮质醇水平的影响尚不一致，需要更多研究来明确其作用 61。这表明营养补充对皮质醇的调节是一个复杂的过程，不同成分可能产生不同的甚至个体化的效果。
4.2 药物与技术干预
除了非药物干预手段，药物和先进技术在调节皮质醇水平、管理过劳状态方面也发挥着日益重要的作用。这些干预通常针对HPA轴的特定环节或通过实时监测提供个性化管理。
4.2.1 肾上腺功能替代治疗
对于长期过劳导致HPA轴功能严重受损，进而发展为临床上明确的肾上腺功能不全（Adrenal Insufficiency, AI）的个体，激素替代治疗是标准且必要的干预措施 62。肾上腺功能不全是一种以肾上腺皮质皮质醇分泌不足为特征的病症，根据病因可分为原发性、继发性或三发性 62。尽管“肾上腺疲劳”的概念在医学界尚存争议，不被主流内分泌学界认可为一种独立的疾病实体，但在某些长期高压、过度应激的个体中，确实可能出现功能性皮质醇分泌不足，尤其是在面临急性应激时，其HPA轴反应迟钝或不足。
激素替代治疗的主要目标是模拟生理性的皮质醇昼夜分泌节律，以维持正常的生理功能并预防肾上腺危象 6263。通常采用氢化可的松（Hydrocortisone）进行替代，因为氢化可的松是合成皮质醇的结构类似物，具有与内源性皮质醇相似的药代动力学特性。治疗方案会根据患者的日常需求进行个体化调整，以尽可能接近生理性皮质醇分泌模式，通常分多次服用，以模拟早晨高峰和夜间低谷 62。
然而，尽管替代治疗能显著改善患者症状，但长期非生理剂量的糖皮质激素替代也可能带来一些副作用，如潜在的认知功能障碍风险。研究指出，肾上腺功能不全患者在接受常规或改良释放型糖皮质激素替代治疗时，由于暂时性的皮质醇过高或过低，可能会影响认知功能，包括记忆、注意力和执行功能等方面 64。因此，如何精确地个体化调整剂量，以在缓解症状和最小化副作用之间取得平衡，仍是临床研究的重点。
4.2.2 新型药物研发
随着对HPA轴调控机制理解的深入，针对皮质醇异常的新型药物研发也取得了一定进展，主要集中在调节HPA轴过度激活或恢复其正常功能。
CRF受体拮抗剂 是一种备受关注的新型药物类别。促肾上腺皮质激素释放激素（CRF）是HPA轴的“启动器”，由下丘脑分泌，作用于垂体上的CRF受体，从而启动ACTH和皮质醇的释放。在慢性应激和某些精神疾病中，CRF系统可能过度活跃，导致HPA轴长期过度激活和皮质醇水平升高。CRF受体拮抗剂通过阻断CRF与其受体的结合，从而抑制HPA轴的过度激活，理论上可以有效降低过高的皮质醇水平，并改善与HPA轴紊乱相关的症状，如焦虑、抑郁和应激相关疾病。例如，Crinecerfont（一种新型CRF1受体拮抗剂）在治疗内源性库欣综合征（一种皮质醇过高疾病）的临床试验中显示出降低皮质醇水平的潜力。虽然这类药物目前主要用于治疗皮质醇过高的疾病，但其原理为未来调控过劳初期HPA轴过度激活提供了新的思路。
此外，针对特定神经递质系统（如血清素、去甲肾上腺素）或炎症通路（如细胞因子抑制剂）的药物，也可能通过间接调节HPA轴活性来影响皮质醇水平和改善过劳症状。然而，这些药物的研发仍处于早期阶段，需要更多的临床研究来验证其在过劳控制中的有效性和安全性。
4.2.3 可穿戴设备监测
随着生物传感器和可穿戴技术的发展，实时监测皮质醇水平成为可能，这为过劳的早期预警和个性化干预提供了创新工具。传统的皮质醇测量方法（血液、尿液、唾液）通常是离线且间歇性的，难以捕捉皮质醇的动态变化和昼夜节律。而可穿戴设备则可以实现连续、无创的实时监测。
目前，基于唾液和汗液的皮质醇可穿戴传感器是研究热点。唾液皮质醇与血浆游离皮质醇水平高度相关，且采集方便。汗液作为一种易于获取的生物流体，其皮质醇浓度虽然低于血液或唾液，但可以实现更长时间的连续监测。例如，一些新型可穿戴生物传感器，如涂覆有抗体的有机电化学晶体管，已能在高离子强度的汗液中实现高灵敏度的皮质醇检测，并在5分钟内完成点护理式检测，为个性化健康监测提供了可能 65。另一项系统综述也强调了可穿戴生物传感器在实时测量汗液生物标志物（包括皮质醇）以监测压力和疲劳方面的潜力 66。
这些可穿戴设备通过集成微流控技术和电化学生物传感器，能够将汗液或唾液中的皮质醇浓度转化为电信号，并实时传输到智能手机或云平台进行数据分析。结合机器学习算法，可以识别个体皮质醇节律的异常模式，并在过劳症状显现之前发出预警。例如，如果个体的清晨皮质醇峰值持续钝化或日间皮质醇下降趋势异常，系统可以提示用户可能存在慢性压力或过度疲劳的风险。这种实时、个性化的监测不仅有助于个体及时调整生活方式、寻求干预，也为临床医生提供了更全面的患者生理状态数据，从而制定更精准的过劳管理策略。
5. 争议与未来研究方向
5.1 伪内分泌概念的澄清
在探讨皮质醇与慢性疲劳及过劳的关系时，必须提及一个长期存在争议且未经验证的“伪内分泌”概念——“肾上腺疲劳”（Adrenal Fatigue）。这个概念在互联网和大众媒体中广为流传，声称由于长期慢性应激，肾上腺功能耗竭，导致皮质醇分泌不足，从而引起一系列非特异性症状，如疲劳、睡眠障碍、注意力不集中、体重增加或减轻等。许多声称患有“肾上腺疲劳”的个体基于此概念寻求诊断和治疗，包括未经证实的唾液皮质醇测试和非循证的营养补充剂或腺体提取物疗法。
然而，主流医学界，特别是内分泌学界，普遍不认可“肾上腺疲劳”为一种独立的、经过科学验证的疾病实体 67。全球主要的内分泌学会，包括内分泌学会（The Endocrine Society）和美国内分泌医师协会（AACE），均明确指出“肾上腺疲劳”缺乏科学依据。他们强调，临床上已知的、明确的肾上腺皮质功能减退症（如艾迪生病，Addison's disease）是由于肾上腺结构或功能受损导致的皮质醇分泌不足，其诊断需要严格的实验室检测（如ACTH刺激试验）和临床评估，并且需要规范的激素替代治疗 67。与此相比，“肾上腺疲劳”的诊断主要依赖非验证的在线问卷和唾液皮质醇曲线，而其所谓的治疗方案也缺乏严谨的临床证据支持，甚至可能存在风险 67。例如，不恰当的激素补充可能导致医源性库欣综合征，或抑制内源性皮质醇分泌，反而引发真正的肾上腺功能不全。
这一“伪内分泌”概念的盛行，对临床诊断造成了显著干扰，主要体现在以下几个方面：
- 延误正确诊断与治疗： 患者可能因相信“肾上腺疲劳”而延误了对其他潜在疾病（如抑郁症、甲状腺功能减退、睡眠呼吸暂停等）的诊断和治疗，这些疾病可能与“肾上腺疲劳”的症状相似。
- 非标准化检测的误导： 唾液皮质醇测试虽然在研究中被广泛应用，但其诊断标准、样本采集和分析方法需要严格标准化 68。针对“肾上腺疲劳”的唾液测试常常缺乏质量控制，其结果可能不准确或被误读，导致不必要的焦虑和干预。例如，皮质醇测量方法的灵敏度和特异性会显著影响诊断标准，尤其是在地塞米松抑制后的血浆皮质醇阈值 69。此外，检测方法的不同（如单克隆抗体与多克隆抗体检测）也会导致诊断率的显著差异，这强调了皮质醇检测标准化的重要性 7071。
- 不当干预的潜在危害： 未经证实的治疗方案，如大剂量维生素、草药补充剂，甚至不正规的激素补充，不仅可能无效，还可能产生有害的副作用 67。
因此，在探讨皮质醇与过劳的关系时，强调皮质醇检测的标准化和临床诊断的严谨性至关重要。专业的医学评估应基于循证医学原则，采用标准化且经过验证的测试方法（如血浆皮质醇、24小时尿游离皮质醇、ACTH刺激试验等），并结合全面的临床表现来评估HPA轴功能。对于疲劳症状，应首先排除其他已知的生理和心理疾病，并采纳基于证据的生活方式干预和心理支持，而非轻信未经证实的“肾上腺疲劳”理论 67。认识到“肾上腺疲劳”是一个伪科学概念，有助于引导患者获得正确的诊断和有效的治疗，避免不必要的健康风险。
5.2 研究异质性与精准干预
在皮质醇与慢性疲劳和过劳关系的研究中，一个显著的挑战是研究结果的异质性。这种异质性主要来源于皮质醇测量方法的差异、研究人群特征（如性别、年龄、种族、共病情况）的多样性，以及疲劳定义和评估标准的非统一性。
1. 皮质醇测量方法的差异：
皮质醇可以在多种生物样本中进行测量，包括血液、尿液、唾液、毛发甚至汗液。每种方法都有其优缺点，且反映了不同时间尺度的皮质醇水平：
- 血浆皮质醇： 反映瞬时（采样时）的皮质醇水平，受应激、进食等即时因素影响较大，且受皮质醇结合蛋白（CBG）的影响。例如，口服避孕药（OCP）会显著升高CBG水平，导致血浆总皮质醇升高，但游离皮质醇可能不受影响或受影响较小 72。
- 尿液游离皮质醇（UFC）： 反映24小时内 HPA 轴的平均活性，能够整合昼夜节律波动，但采集过程可能受依从性影响。有研究显示，CFS 患者的尿液皮质醇及其代谢产物排泄量与对照组无显著差异，这与一些血浆或唾液研究的结果相悖，提示皮质醇代谢速率可能在CFS患者中更快 73。
- 唾液皮质醇： 测量的是游离的、具有生物活性的皮质醇，采样方便且无创，适用于多次采集以绘制昼夜节律曲线。唾液皮质醇与血浆游离皮质醇高度相关，尤其在皮质醇水平低于CBG饱和点时 74。然而，唾液皮质醇的绝对值可能因采集时间、活动水平、进食等因素而波动，且不同实验室的测量方法和参考范围可能存在差异。
- 毛发皮质醇： 提供过去数周到数月皮质醇累积水平的指标，能够反映慢性应激暴露。毛发皮质醇的测量避免了瞬时波动的影响，但在反映急性应激方面不如血浆或唾液敏感 75。
这些测量方法的选择直接影响了研究结果的解释。例如，一项研究可能发现CFS患者的唾液皮质醇峰值钝化，而另一项研究可能发现其24小时尿液皮质醇正常。这种差异部分解释了CFS皮质醇研究中结果不一致的现象。
2. 人群特征导致的结果差异：
个体差异对皮质醇水平及其应激反应有显著影响，这加剧了研究结果的异质性。
- 性别差异： 皮质醇水平和HPA轴功能存在明显的性别差异。研究表明，女性在某些应激反应中皮质醇水平可能更高，且在抑郁症中，女性和男性的糖皮质激素受体（GRs）和盐皮质激素受体（MRs）在HPA轴中的作用可能不同 76。在儿童中，女孩和年龄较小的儿童在胰高血糖素刺激试验中表现出更高的皮质醇峰值 77。这些差异意味着在研究过劳和皮质醇时，需要对男女分层分析，并考虑激素环境（如月经周期、妊娠、更年期）的影响 78。
- 年龄差异： HPA轴功能随年龄增长而变化。婴儿期皮质醇水平和应激反应模式与产前心理压力相关 79，且在儿童中，年龄越小其皮质醇峰值越高 77。这些变化提示HPA轴功能在不同年龄阶段的基线水平和应激反应模式均有所不同。
- 共病情况： 许多慢性疾病，特别是精神疾病（如抑郁症、焦虑症）和慢性炎症性疾病，本身就会影响HPA轴功能和皮质醇水平。在研究慢性疲劳或过劳时，若未充分控制这些共病，可能会混淆结果。
- 遗传背景： 个体对皮质醇的敏感性和代谢能力也受到遗传因素的影响，进一步增加了研究结果的异质性。
精准干预的未来方向：
为了克服现有研究的异质性并实现更精准的干预，未来的研究需要采取多维度、系统化的方法：
标准化测量与多模态数据整合：
细化人群分型与个体化干预：
- 基于生物标志物的分型： 根据皮质醇水平、HPA轴应激反应模式、炎症标志物、线粒体功能等生物学指标，对慢性疲劳和过劳患者进行更精细的分型。例如，区分以皮质醇升高为主的初期过劳、以皮质醇降低为主的后期过劳，以及不同性别、年龄、遗传背景下的亚型。
- 多组学驱动的精准治疗： 基于患者的独特多组学特征，开发和实施个体化的干预策略。例如，对于炎症水平高的患者，可能需要抗炎治疗；对于线粒体功能障碍的患者，可能需要线粒体支持性营养补充 81。对于HPA轴过度激活的个体，可考虑CRF受体拮抗剂等靶向药物；对于HPA轴反应不足的个体，则需更侧重生活方式干预和心理支持。
- 纵向研究与预测模型： 开展长期纵向研究，追踪个体皮质醇动态变化与疲劳进展的关系，并利用机器学习等先进的生物信息学工具，构建能够预测过劳风险和治疗反应的精准模型 80。
通过整合多组学数据、实施标准化测量、进行精细的人群分型以及开发个性化干预方案，未来的研究有望更全面地揭示皮质醇与慢性疲劳和过劳之间的复杂关联，并为临床实践提供更有效、更精准的控制策略。
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参考文献
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Michael J Lawrence, Erika J Eliason, Aaron J Zolderdo, et al.
Fish Physiol Biochem. 2019 Dec;45(6):1813-1828. doi: 10.1007/s10695-019-00680-z. Epub 2019 Jul 12.
Acute elevation of cortisol via activation of the hypothalamic-pituitary-interrenal (HPI) axis aids the fish in dealing with a stressor. However, chronic elevation of cortisol has detrimental effects and has been studied extensively in lab settings. However, data pertaining to wild teleosts are lacking. Here, we characterized the metabolic consequences of prolonged cortisol elevation (96 h) in wild-caught pumpkinseed (Lepomis gibbosus). Pumpkinseed were implanted with cocoa butter alone (sham) or containing cortisol (25 mg kg body weight), and at 24, 48, 72, and 96 h, tissue samples were collected, whole-body ammonia excretion was determined, and whole-organism metabolism was assessed using intermittent flow respirometry. Cortisol-treated pumpkinseed exhibited the highest plasma cortisol concentration at 24 h post-implantation, with levels decreasing over the subsequent time points although remaining higher than in sham-treated fish. Cortisol-treated fish exhibited higher standard and maximal metabolic rates than sham-treated fish, but the effect of cortisol treatment on aerobic scope was negligible. Indices of energy synthesis/mobilization, including blood glucose concentrations, hepatosomatic index, hepatic glycogen concentrations, and ammonia excretion rates, were higher in cortisol-treated fish compared with controls. Our work suggests that although aerobic scope was not diminished by prolonged elevation of cortisol levels, higher metabolic expenditures may be of detriment to the animal's performance in the longer term.
9Chronic Stress and Diabetes Mellitus: Interwoven Pathologies.PubMed
Vivek Kumar Sharma, Thakur Gurjeet Singh
Curr Diabetes Rev. 2020;16(6):546-556. doi: 10.2174/1573399815666191111152248.
Stress threatens the homeostasis and mobilizes a plethora of adaptive physiological and behavioral changes via the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The HPA axis influences the pituitary gland, hypothalamus and adrenal gland via a complex set of positive and negative feedback system. The feedback system operates in a well regulated neuroendocrine manner to reestablish the threatened body equilibrium. The HPA axis secreted major product is a glucocorticoid (cortisol) which is kept within a physiologically optimal range and serves to accomplish the various physiological functions crucial for survival. In chronically stressed individuals dishabituation of HPA axis is followed by increased release of glucocorticoids and catecholamines. Higher secretion of glucocorticoids influences glucose metabolism by promoting gluconeogenesis in the liver, suppressing glucose uptake (adipocytes and skeletal muscles), promoting lipolysis in adipocytes, suppressing insulin secretion, inflicting insulin resistance and inflammation. These biological changes alter neuroendocrine mechanisms and lead to maladaptive congregation of events that form the underlying cause of development of Type 2 diabetes (T2D). The currently reviewed evidences advocate that targeting stress mediated hypersecretion of glucocorticoids may be a viable approach for the treatment of T2D and to reinstate glucose homeostasis.
11Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation.PubMed
Kara E Hannibal, Mark D Bishop
Phys Ther. 2014 Dec;94(12):1816-25. doi: 10.2522/ptj.20130597. Epub 2014 Jul 17.
Pain is a primary symptom driving patients to seek physical therapy, and its attenuation commonly defines a successful outcome. A large body of evidence is dedicated to elucidating the relationship between chronic stress and pain; however, stress is rarely addressed in pain rehabilitation. A physiologic stress response may be evoked by fear or perceived threat to safety, status, or well-being and elicits the secretion of sympathetic catecholamines (epinephrine and norepinepherine) and neuroendocrine hormones (cortisol) to promote survival and motivate success. Cortisol is a potent anti-inflammatory that functions to mobilize glucose reserves for energy and modulate inflammation. Cortisol also may facilitate the consolidation of fear-based memories for future survival and avoidance of danger. Although short-term stress may be adaptive, maladaptive responses (eg, magnification, rumination, helplessness) to pain or non-pain-related stressors may intensify cortisol secretion and condition a sensitized physiologic stress response that is readily recruited. Ultimately, a prolonged or exaggerated stress response may perpetuate cortisol dysfunction, widespread inflammation, and pain. Stress may be unavoidable in life, and challenges are inherent to success; however, humans have the capability to modify what they perceive as stressful and how they respond to it. Exaggerated psychological responses (eg, catastrophizing) following maladaptive cognitive appraisals of potential stressors as threatening may exacerbate cortisol secretion and facilitate the consolidation of fear-based memories of pain or non-pain-related stressors; however, coping, cognitive reappraisal, or confrontation of stressors may minimize cortisol secretion and prevent chronic, recurrent pain. Given the parallel mechanisms underlying the physiologic effects of a maladaptive response to pain and non-pain-related stressors, physical therapists should consider screening for non-pain-related stress to facilitate treatment, prevent chronic disability, and improve quality of life.
12The role of cortisol in immunosuppression in subarachnoid haemorrhage.PubMed
Margaret E Hoadley, James Galea, Navneet Singh, et al.
Eur J Med Res. 2023 Aug 29;28(1):303. doi: 10.1186/s40001-023-01222-3.
BACKGROUND: We sought to determine the extent to which cortisol suppressed innate and T cell-mediated cytokine production and whether it could be involved in reducing peripheral cytokine production following subarachnoid haemorrhage (SAH). METHODS: Whole blood from healthy controls, patients with SAH and healthy volunteers was stimulated with lipopolysaccharide (LPS), to stimulate innate immunity, or phytohaemagglutinin (PHA), to stimulate T cell-mediated immunity. Varying concentrations of cortisol were included, with or without the cortisol antagonist RU486. Concentration of interleukin-6 (IL-6), IL-1β and tumour necrosis factor-alpha) TNFα were determined as a measure of innate immunity. IL-6, IL-17 (interferon gamma) IFNƔ and IL-17 were determined as an indicator of T cell-mediated immunity. RESULTS: Suppression of innate responses to LPS was apparent in whole blood from SAH patients, relative to healthy controls, and TNFα production was inversely correlated with plasma cortisol concentration. Cytokine production in whole blood from healthy volunteers was inhibited by cortisol concentrations from 0.33 µM, or 1 µM and above, and these responses were effectively reversed by the cortisol antagonist RU-486. In SAH patients, RU-486 reversed suppression of innate TNF-α and IL-6 responses, but not IL-1ß or T cell-mediated responses. CONCLUSION: These data suggest that cortisol may play a role in reducing innate, but not T cell-mediated immune responses in patients with injuries such as SAH and that cortisol antagonists could be effective in boosting early innate responses.
13[Neuroendocrine immunomodulation].PubMed
P N Uchakin, O N Uchakina, B V Tobin, et al.
Vestn Ross Akad Med Nauk. 2007(9):26-32.
Close interaction between the immune and nervous systems is well documented. The ability of immunocompetent cells to express receptors to neuroendocrine mediators as well as secrete many of them is proved. The current literature suggests that the hormones of the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonodal axes play the most significant role in the regulation of immune responsiveness. On the other hand, the immune system communicates with the CNS directly through the cytokines that are able to cross the blood-brain barrier, or directly via the nervus vagus, as well as via secondary messengers. Receptors to a number of cytokines have been found in the nervous tissue. Moreover, glial cells are able to secrete cytokines in the amount significant enough for at least autocrine action. In this article, the authors review the role of the "major" stress hormones such as cortisol, DHEA, growth hormone in the regulation of immune response, as well as neuro- and psychotropic properties of two major groups of cytokines that support cell-mediated (Type 1) and humoral (Type 2) immune reactions. This review emphasizes neuro-endocrine-immune interactions in response to infection both under laboratory and clinical conditions.
14Neural regulation of endocrine and autonomic stress responses.PubMed
Yvonne M Ulrich-Lai, James P Herman
Nat Rev Neurosci. 2009 Jun;10(6):397-409. doi: 10.1038/nrn2647.
The survival and well-being of all species requires appropriate physiological responses to environmental and homeostatic challenges. The re- establishment and maintenance of homeostasis entails the coordinated activation and control of neuroendocrine and autonomic stress systems. These collective stress responses are mediated by largely overlapping circuits in the limbic forebrain, the hypothalamus and the brainstem, so that the respective contributions of the neuroendocrine and autonomic systems are tuned in accordance with stressor modality and intensity. Limbic regions that are responsible for regulating stress responses intersect with circuits that are responsible for memory and reward, providing a means to tailor the stress response with respect to prior experience and anticipated outcomes.
15Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?PubMed
Jessica H Lee, Emily Jane Meyer, Marni Anne Nenke, et al.
J Clin Endocrinol Metab. 2024 Aug 13;109(9):2161-2172. doi: 10.1210/clinem/dgae412.
Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.
16Sleep deprivation and stress: a reciprocal relationship.PubMed
Mathieu Nollet, William Wisden, Nicholas P Franks
Interface Focus. 2020 Jun 6;10(3):20190092. doi: 10.1098/rsfs.2019.0092. Epub 2020 Apr 17.
Sleep is highly conserved across evolution, suggesting vital biological functions that are yet to be fully understood. Animals and humans experiencing partial sleep restriction usually exhibit detrimental physiological responses, while total and prolonged sleep loss could lead to death. The perturbation of sleep homeostasis is usually accompanied by an increase in hypothalamic-pituitary-adrenal (HPA) axis activity, leading to a rise in circulating levels of stress hormones (e.g. cortisol in humans, corticosterone in rodents). Such hormones follow a circadian release pattern under undisturbed conditions and participate in the regulation of sleep. The investigation of the consequences of sleep deprivation, from molecular changes to behavioural alterations, has been used to study the fundamental functions of sleep. However, the reciprocal relationship between sleep and the activity of the HPA axis is problematic when investigating sleep using traditional sleep-deprivation protocols that can induce stress . This is especially true in studies using rodents in which sleep deprivation is achieved by exogenous, and potentially stressful, sensory-motor stimulations that can undoubtedly confuse their conclusions. While more research is needed to explore the mechanisms underlying sleep loss and health, avoiding stress as a confounding factor in sleep-deprivation studies is therefore crucial. This review examines the evidence of the intricate links between sleep and stress in the context of experimental sleep deprivation, and proposes a more sophisticated research framework for sleep-deprivation procedures that could benefit from recent progress in biotechnological tools for precise neuromodulation, such as chemogenetics and optogenetics, as well as improved automated real-time sleep-scoring algorithms.
17Metabolic consequences of sleep and sleep loss.PubMed
Eve Van Cauter, Karine Spiegel, Esra Tasali, et al.
Sleep Med. 2008 Sep;9 Suppl 1(0 1):S23-8. doi: 10.1016/S1389-9457(08)70013-3.
Reduced sleep duration and quality appear to be endemic in modern society. Curtailment of the bedtime period to minimum tolerability is thought to be efficient and harmless by many. It has been known for several decades that sleep is a major modulator of hormonal release, glucose regulation and cardiovascular function. In particular, slow wave sleep (SWS), thought to be the most restorative sleep stage, is associated with decreased heart rate, blood pressure, sympathetic nervous activity and cerebral glucose utilization, compared with wakefulness. During SWS, the anabolic growth hormone is released while the stress hormone cortisol is inhibited. In recent years, laboratory and epidemiologic evidence have converged to indicate that sleep loss may be a novel risk factor for obesity and type 2 diabetes. The increased risk of obesity is possibly linked to the effect of sleep loss on hormones that play a major role in the central control of appetite and energy expenditure, such as leptin and ghrelin. Reduced leptin and increased ghrelin levels correlate with increases in subjective hunger when individuals are sleep restricted rather than well rested. Given the evidence, sleep curtailment appears to be an important, yet modifiable, risk factor for the metabolic syndrome, diabetes and obesity. The marked decrease in average sleep duration in the last 50 years coinciding with the increased prevalence of obesity, together with the observed adverse effects of recurrent partial sleep deprivation on metabolism and hormonal processes, may have important implications for public health.
18The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial.PubMed
Behnood Abbasi, Masud Kimiagar, Khosro Sadeghniiat, et al.
J Res Med Sci. 2012 Dec;17(12):1161-9.
BACKGROUND: Nearly 50% of older adults have insomnia, with difficulty in getting to sleep, early awakening, or feeling unrefreshed on waking. With aging, several changes occur that can place one at risk for insomnia, including age-related changes in various circadian rhythms, environmental and lifestyle changes, and decreased nutrients intake, absorption, retention, and utilization. The natural N-methyl-D-aspartic acid (NMDA) antagonist and GABA agonist, Mg(2+), seems to play a key role in the regulation of sleep. The objective of this study was to determine the efficacy of magnesium supplementation to improve insomnia in elderly. MATERIALS AND METHODS: A double-blind randomized clinical trial was conducted in 46 elderly subjects, randomly allocated into the magnesium or the placebo group and received 500 mg magnesium or placebo daily for 8 weeks. Questionnaires of insomnia severity index (ISI), physical activity, and sleep log were completed at baseline and after the intervention period. Anthropometric confounding factors, daily intake of magnesium, calcium, potassium, caffeine, calories form carbohydrates, and total calorie intake, were obtained using 24-h recall for 3 days. Blood samples were taken at baseline and after the intervention period for analysis of serum magnesium, renin, melatonin, and cortisol. Statistical analyses were performed using SPSS19 and P values < 0.05 were considered as statistically significant. RESULTS: No significant differences were observed in assessed variables between the two groups at the baseline. As compared to the placebo group, in the experimental group, dietary magnesium supplementation brought about statistically significant increases in sleep time (P = 0.002), sleep efficiency (P = 0.03), concentration of serum renin (P < 0.001), and melatonin (P = 0.007), and also resulted in significant decrease of ISI score (P = 0.006), sleep onset latency (P = 0.02) and serum cortisol concentration (P = 0.008). Supplementation also resulted in marginally between-group significant reduction in early morning awakening (P = 0.08) and serum magnesium concentration (P = 0.06). Although total sleep time (P = 0.37) did not show any significant between-group differences. CONCLUSION: Supplementation of magnesium appears to improve subjective measures of insomnia such as ISI score, sleep efficiency, sleep time and sleep onset latency, early morning awakening, and likewise, insomnia objective measures such as concentration of serum renin, melatonin, and serum cortisol, in elderly people.
19Loneliness and health: potential mechanisms.PubMed
John T Cacioppo, Louise C Hawkley, L Elizabeth Crawford, et al.
Psychosom Med. 2002 May-Jun;64(3):407-17. doi: 10.1097/00006842-200205000-00005.
OBJECTIVE: Two studies using cross-sectional designs explored four possible mechanisms by which loneliness may have deleterious effects on health: health behaviors, cardiovascular activation, cortisol levels, and sleep. METHODS: In Study 1, we assessed autonomic activity, salivary cortisol levels, sleep quality, and health behaviors in 89 undergraduate students selected based on pretests to be among the top or bottom quintile in feelings of loneliness. In Study 2, we assessed blood pressure, heart rate, salivary cortisol levels, sleep quality, and health behaviors in 25 older adults whose loneliness was assessed at the time of testing at their residence. RESULTS: Total peripheral resistance was higher in lonely than nonlonely participants, whereas cardiac contractility, heart rate, and cardiac output were higher in nonlonely than lonely participants. Lonely individuals also reported poorer sleep than nonlonely individuals. Study 2 indicated greater age-related increases in blood pressure and poorer sleep quality in lonely than nonlonely older adults. Mean salivary cortisol levels and health behaviors did not differ between groups in either study. CONCLUSIONS: Results point to two potentially orthogonal predisease mechanisms that warrant special attention: cardiovascular activation and sleep dysfunction. Health behavior and cortisol regulation, however, may require more sensitive measures and large sample sizes to discern their roles in loneliness and health.
20The effects of exercise intensity on the cortisol response to a subsequent acute psychosocial stressor.PubMed
A Caplin, F S Chen, M R Beauchamp, et al.
Psychoneuroendocrinology. 2021 Sep;131:105336. doi: 10.1016/j.psyneuen.2021.105336. Epub 2021 Jun 18.
OBJECTIVE: The aim of this experimental study was to determine the extent to which the intensity of a single 30 min bout of exercise alters the salivary cortisol (sCort) response to a subsequently induced acute psychosocial stressor. The study further aimed to elucidate a physiological mechanism through which exercise intensity exerts stress-mitigating effects. METHODS: Eighty-three healthy men (M = 21.04 SD = 2.89) were randomly assigned to exercise on a treadmill at either 30%, 50% or 70% of their heart rate reserve (HRR) for 30 min and then underwent the Trier Social Stress Test 45 min later. sCort was measured repeatedly throughout and following the exercise bout and stressor task. RESULTS: ANCOVA and Multilevel Growth Curve Analysis determined that vigorous (70% HRR) exercise elicited dampened sCort responses to the stressor task, marked by lower total sCort levels, diminished sCort reactivity, and faster recovery to baseline values, as compared to less intense exercise. Moreover, exercise elicited a sCort response in proportion to the intensity at which it was performed, and this exercise-associated HPA-axis response was inversely proportional to the sCort response to the subsequent stressor task. CONCLUSIONS: This study revealed that exercise-intensity dampens the HPA-axis stress response in a dose-dependent manner, with evidence that the cortisol released from exercising intensely suppresses the subsequent cortisol response to a psychosocial stressor.
21The effects of physical activity on cortisol and sleep: A systematic review and meta-analysis.PubMed
Len De Nys, Kerry Anderson, Esther F Ofosu, et al.
Psychoneuroendocrinology. 2022 Sep;143:105843. doi: 10.1016/j.psyneuen.2022.105843. Epub 2022 Jun 24.
BACKGROUND: Managing stress and having good quality sleep are inter-related factors that are essential for health, and both factors seem to be affected by physical activity. Although there is an established bidirectional relationship between stress and sleep, remarkably few studies have been designed to examine the effects of physical activity on cortisol, a key biomarker for stress, and sleep. Research is particularly scarce in older people despite both sleep and cortisol changing with age. This systematic literature review addresses this gap. METHODS: A systematic review was conducted following the PRISMA guidelines. Original, peer-reviewed records of intervention studies such as randomized controlled trials (RCTs) and non-RCTs with relevant control groups were eligible for inclusion. The Participant, Intervention, Comparison, Outcome (PICO) characteristics were (1) adults or older adults (2) physical activity programmes of any duration, (3) controls receiving no intervention or controls included in a different programme, (4) cortisol measurement, and subjective or objective measures of sleep. RESULTS: Ten original studies with low-to-moderate risk of bias were included. Findings from this review indicated with moderate- and low-certainty evidence, respectively, that physical activity was an effective strategy for lowering cortisol levels (SMD [95% CI] = -0.37 [-0.52, -0.21] p < .001) and improving sleep quality (SMD [95% CI] = -0.30 [-0.56, -0.04], p = .02). Caution is needed to generalize these findings to the general population, as included trials were predominantly participants with breast cancer, included few males and no older adults. CONCLUSION: Cortisol regulation and sleep quality are intertwined, and physical activity programmes could improve both in several ways. Further, physical activity may benefit adults with long term conditions or current poor (mental) health states the most, although more research is needed to support this claim fully. Few intervention studies have examined the inter-relationship between cortisol and sleep outcomes in males or older adults, indicating fruitful enquiry for future research.
22Low-carbohydrate diets and men's cortisol and testosterone: Systematic review and meta-analysis.PubMed
Joseph Whittaker, Miranda Harris
Nutr Health. 2022 Dec;28(4):543-554. doi: 10.1177/02601060221083079. Epub 2022 Mar 7.
Low-carbohydrate diets may have endocrine effects, although individual studies are conflicting. Therefore, a review was conducted on the effects of low- versus high-carbohydrate diets on men's testosterone and cortisol. The review was registered on PROSPERO (CRD42021255957). The inclusion criteria were: intervention study, healthy adult males, and low-carbohydrate diet: ≤35% carbohydrate. Eight databases were searched from conception to May 2021. Cochrane's risk of bias tool was used for quality assessment. Random-effects, meta-analyses using standardized mean differences and 95% confidence intervals, were performed with Review Manager. Subgroup analyses were conducted for diet duration, protein intake, and exercise duration. Twenty-seven studies were included, with a total of 309 participants. Short-term (<3 weeks), low- versus high-carbohydrate diets moderately increased resting cortisol (0.41 [0.16, 0.66], < 0.01). Whereas, long-term (≥3 weeks), low-carbohydrate diets had no consistent effect on resting cortisol. Low- versus high-carbohydrate diets resulted in much higher post-exercise cortisol, after long-duration exercise (≥20 min): 0 h (0.78 [0.47, 1.1], < 0.01), 1 h (0.81 [0.31, 1.31], < 0.01), and 2 h (0.82 [0.33, 1.3], < 0.01). Moderate-protein (<35%), low-carbohydrate diets had no consistent effect on resting total testosterone, however high-protein (≥35%), low-carbohydrate diets greatly decreased resting (-1.08 [-1.67, -0.48], < 0.01) and post-exercise total testosterone (-1.01 [-2, -0.01] = 0.05). Resting and post-exercise cortisol increase during the first 3 weeks of a low-carbohydrate diet. Afterwards, resting cortisol appears to return to baseline, whilst post-exercise cortisol remains elevated. High-protein diets cause a large decrease in resting total testosterone (∼5.23 nmol/L).
23Effects of a Mediterranean Diet Intervention on Maternal Stress, Well-Being, and Sleep Quality throughout Gestation-The IMPACT-BCN Trial.PubMed
Irene Casas, Ayako Nakaki, Rosalia Pascal, et al.
Nutrients. 2023 May 18;15(10):2362. doi: 10.3390/nu15102362.
Stress and anxiety are frequent occurrences among pregnant women. We aimed to evaluate the effects of a Mediterranean diet intervention during pregnancy on maternal stress, well-being, and sleep quality throughout gestation. In a randomized clinical trial, 1221 high-risk pregnant women were randomly allocated into three groups at 19-23 weeks' gestation: a Mediterranean diet intervention, a Mindfulness-Based Stress Reduction program, or usual care. All women who provided self-reported life-style questionnaires to measure their anxiety (State Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS)), well-being (WHO Five Well Being Index (WHO-5)), and sleep quality (Pittsburgh sleep quality index (PSQI)) at enrollment and at the end of the intervention (34-36 weeks) were included. In a random subgroup of 106 women, the levels of cortisol and related metabolites were also measured. At the end of the intervention (34-36 weeks), participants in the Mediterranean diet group had significantly lower perceived stress and anxiety scores (PSS mean (SE) 15.9 (0.4) vs. 17.0 (0.4), = 0.035; STAI-anxiety mean (SE) 13.6 (0.4) vs. 15.8 (0.5), = 0.004) and better sleep quality (PSQI mean 7.0 ± 0.2 SE vs. 7.9 ± 0.2 SE, = 0.001) compared to usual care. As compared to usual care, women in the Mediterranean diet group also had a more significant increase in their 24 h urinary cortisone/cortisol ratio during gestation (mean 1.7 ± SE 0.1 vs. 1.3 ± SE 0.1, < 0.001). A Mediterranean diet intervention during pregnancy is associated with a significant reduction in maternal anxiety and stress, and improvements in sleep quality throughout gestation.
24The neuroendocrinology of chronic fatigue syndrome and fibromyalgia.PubMed
A J Parker, S Wessely, A J Cleare
Psychol Med. 2001 Nov;31(8):1331-45. doi: 10.1017/s0033291701004664.
BACKGROUND: Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and 5-HT function, make some form of hypothesis (3) most likely. We review the methodology and results of studies of the HPA and other neuroendocrine axes in CFS. METHOD: Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy. A search was also performed on the King's College CFS database, which includes over 3000 relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991). RESULTS: One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function, and enhanced 5-HT function on neuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS. CONCLUSIONS: The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether these changes are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studies of populations at risk for CFS will help to resolve these issues.
25Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome.PubMed
Andrew S Papadopoulos, Anthony J Cleare
Nat Rev Endocrinol. 2011 Sep 27;8(1):22-32. doi: 10.1038/nrendo.2011.153.
The weight of current evidence supports the presence of the following factors related to hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS. Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can increase cortisol. Addressing these factors-for example, with cognitive behavioral therapy-can increase cortisol levels and is probably the first-line approach for correcting HPA axis dysfunction at present, as steroid replacement is not recommended. Given what is now a fairly consistent pattern of findings for the type of HPA axis changes found in CFS, we recommend that future work focuses on improving our understanding of the cause and relevance of these observed changes.
26Urinary free cortisol in chronic fatigue syndrome.PubMed
A J Cleare, D Blair, S Chambers, et al.
Am J Psychiatry. 2001 Apr;158(4):641-3. doi: 10.1176/appi.ajp.158.4.641.
OBJECTIVE: The authors measured 24-hour urinary free cortisol in a group of well-characterized patients with chronic fatigue syndrome. METHOD: They obtained 24-hour urine collections from 121 consecutive clinic patients with chronic fatigue syndrome and 64 comparison subjects without the syndrome. RESULTS: Urinary free cortisol was significantly lower in the subjects with chronic fatigue syndrome regardless of the presence or absence of current or past comorbid psychiatric illness. Lower levels of urinary free cortisol were not related to medication use, sleep disturbance, or disability levels. CONCLUSIONS: There is mild hypocortisolism in chronic fatigue syndrome. Whether a primary feature or secondary to other factors, hypocortisolism may be one factor contributing to the symptoms of chronic fatigue syndrome.
27Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders.PubMed
Lineke M Tak, Anthony J Cleare, Johan Ormel, et al.
Biol Psychol. 2011 May;87(2):183-94. doi: 10.1016/j.biopsycho.2011.02.002. Epub 2011 Feb 18.
Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is the most investigated biological risk marker in functional somatic disorders (FSDs), such as chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS). Our aim was to assess whether there is an association between basal hypocortisolism and FSD and to identify potential moderators of this association. Meta-analysis on 85 studies revealed that although basal cortisol levels were generally lower in FSD subjects compared to controls, this association did not reach statistical significance (SMD -0.07, 95% CI -0.17 to 0.04, p=0.241). However, when the three FSD were assessed separately, statistically significant basal hypocortisolism was observed in CFS subjects compared to controls (SMD -0.14, 95% CI -0.28 to 0.00, p=0.047), but not in FM or IBS. When all potential moderators were entered into a meta-regression analysis, only type of FSD and female gender were significant independent predictors of basal hypocortisolism. In conclusion, we did not find evidence to consider all three main FSD as hypocortisolemic disorders, as significant reduction in basal cortisol compared to healthy controls was only found in CFS and in females with FM, but not in IBS.
28Cortisol levels in chronic fatigue syndrome and atypical depression measured using hair and saliva specimens.PubMed
Andres Herane-Vives, Andrew Papadopoulos, Valeria de Angel, et al.
J Affect Disord. 2020 Apr 15;267:307-314. doi: 10.1016/j.jad.2020.01.146. Epub 2020 Jan 29.
BACKGROUND: Several diagnostic criteria for major depressive disorder (MDE) overlap with those of Chronic Fatigue Syndrome (CFS). Furthermore, atypical MDE (A-MDE), a subtype of MDE characterised by profound fatigue and which has frequently been linked with CFS, exhibits similar low cortisol levels to CFS. However, this result has been only found in specimens designed for measuring acute cortisol levels. In this study, we measure cortisol levels in subjects with CFS and in subjects with A-MDE, without psychiatric comorbidity, using both hair and saliva specimens, to gain a measure of both short and long-term cortisol levels in these two conditions. METHODS: Hair cortisol concentration, representing the cortisol concentration of the previous three months, and salivary cortisol, measured at six time-points across one day and including the cortisol awakening response (CAR), post-awakening delta cortisol and the total daily output, were assessed in an age and gender matched group of 34 controls, 15 subjects with A-MDE and 17 with CFS. RESULTS: CFS (mean 92.2 nmol/l.h, s.d. 33.2 nmol/l.h) and A-MDE (mean 89.1 nmol/l.h, s.d. 22.6 nmol/l.h) subjects both showed lower cortisol total daily output in saliva (AUCg) in comparison to healthy controls (mean 125.5 nmol/l.h, s.d. 40.6 nmol/l.h). However, hair cortisol concentration was not lower than that of controls in either patient group. CFS and A-MDE did not differ from one another on any cortisol measures. CFS subjects reported fewer daily hassles and less severe psychic anxiety symptoms in comparison to A-MDE subjects (all p < 0.05). However, they did not differ in the severity of somatic anxiety symptoms. There was also no difference in the presence of overlapping symptoms such as fatigability and concentration/memory problems between A-MDE and CFS subjects. CONCLUSION: Low levels of cortisol found using short-term measures of daily output may be transient, since cortisol levels were normal when a long-term measure (hair) was studied. This might be explained by a potential cortisol rhythm alteration. Although these disorders have their distinctive depressive and somatic features, they may from part of a wider group of Somatic Symptom Disorders (SSD), given the findings of the same pattern of cortisol secretion in both disorders and increased frequency of overlapping clinical features.
29The hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome.PubMed
F Tanriverdi, Z Karaca, K Unluhizarci, et al.
Stress. 2007 Mar;10(1):13-25. doi: 10.1080/10253890601130823.
The hypothalamo-pituitary-adrenal (HPA) axis plays a major role in the regulation of responses to stress. Human stress-related disorders such as chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stress-related disorders is not clear. Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for the study, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. There is no structural abnormality in the endocrine organs which comprise the HPA axis, thus it seems that hypocortisolemia found in the patients with stress-related disorder is functional. It may be also an adaptive response of the body to chronic stress. In this review, tests used in the assessment of HPA axis function and the HPA axis alterations found in CFS and FMS are discussed in detail.
30The HPA axis and the genesis of chronic fatigue syndrome.PubMed
Anthony J Cleare
Trends Endocrinol Metab. 2004 Mar;15(2):55-9. doi: 10.1016/j.tem.2003.12.002.
Many studies of patients with long-standing chronic fatigue syndrome (CFS) have found alterations to the hypothalamo-pituitary-adrenal (HPA) axis, including mild hypocortisolism, heightened negative feedback and blunted responses to challenge. However, recent prospective studies of high-risk cohorts suggest that there are no HPA axis changes present during the early stages of the genesis of fatiguing illnesses. Moreover, HPA axis changes can be reversed by modifying behavioural features of the illness, such as inactivity, deconditioning and sleep disturbance. Nevertheless, raising levels of cortisol pharmacologically can temporarily alleviate symptoms of fatigue. This article presents the case that there is no specific change to the HPA axis in CFS and that the observed changes are of multifactorial aetiology, with some factors occurring as a consequence of the illness. Nevertheless, the HPA axis might play a role in exacerbating or perpetuating symptoms late on in the course of the illness.
31Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome.PubMed
Filip Van Den Eede, Greta Moorkens, Boudewijn Van Houdenhove, et al.
Neuropsychobiology. 2007;55(2):112-20. doi: 10.1159/000104468. Epub 2007 Jun 27.
There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.
32A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).PubMed
Asher Taccori, Rebekah Maksoud, Natalie Eaton-Fitch, et al.
J Transl Med. 2023 Jul 5;21(1):440. doi: 10.1186/s12967-023-04295-0.
BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls. METHODS: Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17. RESULTS: Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult. CONCLUSIONS: There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.
33Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction.PubMed
Christine Heim, Urs M Nater, Elizabeth Maloney, et al.
Arch Gen Psychiatry. 2009 Jan;66(1):72-80. doi: 10.1001/archgenpsychiatry.2008.508.
CONTEXT: Childhood trauma appears to be a potent risk factor for chronic fatigue syndrome (CFS). Evidence from developmental neuroscience suggests that early experience programs the development of regulatory systems that are implicated in the pathophysiology of CFS, including the hypothalamic-pituitary-adrenal axis. However, the contribution of childhood trauma to neuroendocrine dysfunction in CFS remains obscure. OBJECTIVES: To replicate findings on the relationship between childhood trauma and risk for CFS and to evaluate the association between childhood trauma and neuroendocrine dysfunction in CFS. DESIGN, SETTING, AND PARTICIPANTS: A case-control study of 113 persons with CFS and 124 well control subjects identified from a general population sample of 19 381 adult residents of Georgia. MAIN OUTCOME MEASURES: Self-reported childhood trauma (sexual, physical, and emotional abuse; emotional and physical neglect), psychopathology (depression, anxiety, and posttraumatic stress disorder), and salivary cortisol response to awakening. RESULTS: Individuals with CFS reported significantly higher levels of childhood trauma and psychopathological symptoms than control subjects. Exposure to childhood trauma was associated with a 6-fold increased risk of CFS. Sexual abuse, emotional abuse, and emotional neglect were most effective in discriminating CFS cases from controls. There was a graded relationship between exposure level and CFS risk. The risk of CFS conveyed by childhood trauma further increased with the presence of posttraumatic stress disorder symptoms. Only individuals with CFS and with childhood trauma exposure, but not individuals with CFS without exposure, exhibited decreased salivary cortisol concentrations after awakening compared with control subjects. CONCLUSIONS: Our results confirm childhood trauma as an important risk factor of CFS. In addition, neuroendocrine dysfunction, a hallmark feature of CFS, appears to be associated with childhood trauma. This possibly reflects a biological correlate of vulnerability due to early developmental insults. Our findings are critical to inform pathophysiological research and to devise targets for the prevention of CFS.
34Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues.PubMed
Graziella F Romano, Simona Tomassi, Alice Russell, et al.
Adv Psychosom Med. 2015;34:61-77. doi: 10.1159/000369085. Epub 2015 Mar 30.
There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS). Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined. Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM. Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes. However, to what extent these systems' abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified.
35A new view on hypocortisolism.PubMed
Eva Fries, Judith Hesse, Juliane Hellhammer, et al.
Psychoneuroendocrinology. 2005 Nov;30(10):1010-6. doi: 10.1016/j.psyneuen.2005.04.006.
Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post-traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue. This overview will present data on the development, mechanisms and consequences of hypocortisolism on different bodily systems. We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic-pituitary-adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.
36Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: A psychoneuroendocrinological structural regression model.PubMed
Sara F Milrad, Daniel L Hall, Devika R Jutagir, et al.
Int J Psychophysiol. 2018 Sep;131:124-130. doi: 10.1016/j.ijpsycho.2017.09.009. Epub 2017 Sep 14.
INTRODUCTION: Chronic Fatigue Syndrome (CFS) is a poorly understood illness that is characterized by diverse somatic symptoms, hypothalamic pituitary adrenal (HPA) axis dysfunction and heightened inflammatory indicators. These symptoms are often exacerbated and accompanied by psychological distress states and depression. Since depression is known to be associated with HPA axis dysfunction and greater inflammation, a psychoneuroendocrinological (PNE) model of inflammation was examined in persons diagnosed with CFS in order to uncover underlying biopsychosocial mechanisms in this poorly understood chronic illness. METHODS: Baseline data were drawn from two randomized controlled trials testing the efficacy of different forms of psychosocial intervention, and included psychological questionnaires, di-urnal salivary cortisol, and blood samples. Data were analyzed with structural equation modeling (SEM). RESULTS: The sample (N=265) was mostly middle-aged (M=49.36±10.9, range=20-73years), Caucasian (67.7%), female (81.7%), highly educated (85.5% completed some college, college, or graduate program), and depressed (CES-D M=23.87±12.02, range 2-57). The SEM supporting a psychoneuroendocrinological model of immune dysregulation in CFS fit the data χ (12)=17.725, p=0.1243, RMSEA=0.043, CFI=0.935, SRMR=0.036. Depression was directly related to evening salivary cortisol and inflammation, such that higher evening cortisol predicted greater depressive symptoms (β=0.215, p<0.01) and higher pro-inflammatory cytokines (interleukin-2 [IL-2], IL-6, and tumor necrosis factor-alpha [TNF-α] levels (β=0.185, p<0.05), when controlling for covariates. DISCUSSION: Results highlight the role of depression, cortisol and inflammation in possible biological mechanisms involved in the pathophysiology of CFS. Time-lagged, longitudinal analyses are needed to fully explore these relationships.
37Psychoneurological Symptoms and Biomarkers of Stress and Inflammation in Newly Diagnosed Head and Neck Cancer Patients: A Network Analysis.PubMed
Angelina M M Santoso, Femke Jansen, Carel F W Peeters, et al.
Curr Oncol. 2022 Sep 28;29(10):7109-7121. doi: 10.3390/curroncol29100559.
Psychoneurological symptoms are commonly reported by newly diagnosed head and neck cancer (HNC) patients, yet there is limited research on the associations of these symptoms with biomarkers of stress and inflammation. In this article, pre-treatment data of a multi-center cohort of HNC patients were analyzed using a network analysis to examine connections between symptoms (poor sleep quality, anxiety, depression, fatigue, and oral pain), biomarkers of stress (diurnal cortisol slope), inflammation markers (c-reactive protein [CRP], interleukin [IL]-6, IL-10, and tumor necrosis factor alpha [TNF-α]), and covariates (age and body mass index [BMI]). Three centrality indices were calculated: degree (number of connections), closeness (proximity of a variable to other variables), and betweenness (based on the number of times a variable is located on the shortest path between any pair of other variables). In a sample of 264 patients, poor sleep quality and fatigue had the highest degree index; fatigue and CRP had the highest closeness index; and IL-6 had the highest betweenness index. The model yielded two clusters: a symptoms-cortisol slope-CRP cluster and a IL-6-IL-10-TNF-α-age-BMI cluster. Both clusters were connected most prominently via IL-6. Our findings provide evidence that poor sleep quality, fatigue, CRP, and IL-6 play an important role in the interconnections between psychoneurological symptoms and biomarkers of stress and inflammation in newly diagnosed HNC patients.
38Shuyu decoction exhibits anti-fatigue properties via alleviating exercise-induced immune dysfunction.PubMed
Shujing Zhang, Yuemeng Sun, Jiarou Wang, et al.
J Ethnopharmacol. 2024 Jan 30;319(Pt 2):117259. doi: 10.1016/j.jep.2023.117259. Epub 2023 Sep 30.
ETHNOPHARMACOLOGICAL RELEVANCE: Shuyu decoction (SYD), an effective traditional Chinese medicine (TCM), has been widely used for treating deficiency-related diseases for thousands of years. Meanwhile, exercise-induced fatigue (EF), a common physiological phenomenon observed in physical training, has been treated as a deficient condition in TCM for decades. Currently, not many studies have been conducted on the effect of SYD on EF and little is known about its underlying pharmacological mechanism. AIM OF THE STUDY: This current study was designed to assess the anti-fatigue roles of SYD and explore its effect on exercise-induced immune dysfunction. MATERIALS AND METHODS: Eighteen rats were randomly divided into three groups: normal control (NC) group, model (M) group, and SYD group (27.8 g/kg). The M and SYD group were given treadmill training for 6 weeks. From the fourth week, the SYD group was administered SYD intragastrically for 3 consecutive weeks. After three weeks of treatment, the rats were anesthetized, and the blood and spleen tissue samples were dissected. The blood sample was devoted to the blood biochemical-related indicators, which were used to evaluate the anti-fatigue of SYD. The expression of Interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), IL-17, CD3, and CD4 were detected by ELISA and the level of CD8 of blood was measured through Flow Cytometry (FC). The histopathological changes of spleen tissue samples were determined by Hematoxylin and eosin (H&E) staining and an estimation of CD3, CD4, and CD8 expression of spleen tissues were calculated through FC. RESULTS: Compared with the M group, the SYD group observed an increase in tensile force and the ratio of cortisol to testosterone (TTE/COR), whereas a reduction in the levels of lactic acid (LAC), blood urea nitrogen (BUN), creatine kinase (CK), (P < 0.01 or P < 0.05). ELISA experiments showed that SYD reduced the expressions of IL-6, IL-1β, and TNF-α, IL-17 and increased the expression of IL-10 (P < 0.01 or P < 0.05). In the HE test, SYD treatment transformed the structure of the spleen. FC experiments further showed that SYD increased the expressions of CD3, CD4, and CD8 in blood and spleen tissues (P < 0.01 or P < 0.05). CONCLUSION: Our findings indicate that SYD can alleviate EF by improving inflammation and immunity. However, the relationship between inflammatory factors and the related immune response remains to be further investigated.
39Distinguishing features of long COVID identified through immune profiling.PubMed
Jon Klein, Jamie Wood, Jillian R Jaycox, et al.
Nature. 2023 Nov;623(7985):139-148. doi: 10.1038/s41586-023-06651-y. Epub 2023 Sep 25.
Post-acute infection syndromes may develop after acute viral disease. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
40Pituitary-Adrenal Axis and Peripheral Immune Cell Profile in Long COVID.PubMed
Jaume Alijotas-Reig, Ariadna Anunciacion-Llunell, Enrique Esteve-Valverde, et al.
Biomedicines. 2024 Mar 5;12(3):581. doi: 10.3390/biomedicines12030581.
In Long COVID, dysfunction in the pituitary-adrenal axis and alterations in immune cells and inflammatory status are warned against. We performed a prospective study in a cohort of 42 patients who suffered COVID-19 at least 6 months before attending the Long COVID unit at Althaia Hospital. Based on Post-COVID Functional Status, 29 patients were diagnosed with Long COVID, while 13 were deemed as recovered. The hormones of the pituitary-adrenal axis, adrenocorticotropin stimulation test, and immune cell profiles and inflammatory markers were examined. Patients with Long COVID had significantly lower EuroQol and higher mMRC scores compared to the recovered individuals. Their symptoms included fatigue, myalgia, arthralgia, persistent coughing, a persistent sore throat, dyspnoea, a lack of concentration, and anxiety. We observed the physiological levels of cortisol and adrenocorticotropin in individuals with or without Long COVID. The results of the adrenocorticotropin stimulation test were similar between both groups. The absolute number of neutrophils was lower in the Long COVID patients compared to recovered individuals ( < 0.05). The total count of B lymphocytes remained consistent, but Long COVID patients had a higher percentage of mature B cells compared to recovered participants ( < 0.05) and exhibited a higher percentage of circulating resident memory CD8+ T cells ( < 0.05) and Treg-expressing exonucleases ( < 0.05). Our findings did not identify adrenal dysfunction related to Long COVID, nor an association between adrenal function and clinical symptoms. The data indicated a dysregulation in certain immune cells, pointing to immune activation. No overt hyperinflammation was observed in the Long COVID group.
41Burnout Syndrome in Physicians-Psychological Assessment and Biomarker Research.PubMed
Tanya Deneva, Youri Ianakiev, Donka Keskinova
Medicina (Kaunas). 2019 May 24;55(5):209. doi: 10.3390/medicina55050209.
: Burnout is a syndrome typically occurring in work environments with continuous and chronic stress. Physicians are at increased risk for burnout, as a result of 24-hour work, delayed work-life balance gratification, and the challenges associated with patient care. The aim of the present study was to evaluate the psychological parameters of burnout symptoms in relation to biomarkers of stress among physicians with different medical specialties. : A total of 303 physicians were contacted as potential participants. A comparison group of 111 individuals working outside medicine was used as a control to verify the results. The physicians were specialists in internal medicine, general surgery, pathology, and primary care. Serum cortisol, salivary cortisol, adrenocorticotropic hormone (ACTH), insulin (IRI), and prolactin levels were analyzed by chemiluminescence enzyme immunoassay (Access 2, Beckman Coulter). Fasting glucose in serum and glycated hemoglobin (HbA1C) in whole blood were measured using the automatic analyzer AU 480 Beckman Coulter system. Symptoms of burnout were measured with the Maslach Burnout Inventory (MBI). : The group with burnout presented significantly higher levels of serum and saliva cortisol, ACTH, prolactin, fasting glucose, and HbA1C compared with the control group. The correlation analysis between biomarkers showed a positive correlation with moderate strength between serum and saliva cortisol ( = 0.516, = 0.01),as well as serum and saliva cortisol with ACTH ( = 0.418; = 0.412, = 0.01) and HbA1C ( = 0.382; = 0.395, = 0.01). A weak positive correlation was found between serum and saliva cortisol with prolactin ( = 0.236; = 0.267, < 0.01) and glucose ( = 0.271; = 0.297, < 0.01). In the multiple logistic regression model, saliva cortisol, HbA1C, and age were significantly associated with burnout (chi-square = 16.848, < 0.032). : Our findings demonstrated the interest of exploring biomarkers of stress related to burnout in health professionals.
42The biology of burnout: Causes and consequences.PubMed
Adam Bayes, Gabriela Tavella, Gordon Parker
World J Biol Psychiatry. 2021 Nov;22(9):686-698. doi: 10.1080/15622975.2021.1907713. Epub 2021 Apr 30.
OBJECTIVES: Burnout is a state of exhaustion resulting from prolonged and excessive workplace stress. We sought to examine biological underpinnings of burnout, focussing on mechanisms and physical consequences. METHODS: We searched the literature on burnout and evaluated studies examining biological parameters in patient populations (i.e. 'clinical' burnout) as well as in individuals from the general population judged as having some degree of burnout evaluated using a dimensional approach. RESULTS: Findings suggest that burnout is associated with sustained activation of the autonomic nervous system and dysfunction of the sympathetic adrenal medullary axis, with alterations in cortisol levels. Limited studies have also shown altered immune function and changes in other endocrine systems. Consequences of burnout include increased allostatic load, structural and functional brain changes, excito-toxicity, systemic inflammation, immunosuppression, metabolic syndrome, cardiovascular disease and premature death. Limitations of studies include variability in study populations, low specificity of burnout measures, and mostly cross-sectional studies precluding examination of changes across the course of burnout. CONCLUSIONS: Further examination of biological mechanisms of burnout would benefit from more homogeneous clinical samples, challenge tests and prospective studies. This would assist in differentiation from conditions such as depression and aid with development of specific treatment targets for burnout.
43Overtraining, Exercise, and Adrenal Insufficiency.PubMed
Ka Brooks, Jg Carter
J Nov Physiother. 2013 Feb 16;3(125). doi: 10.4172/2165-7025.1000125.
Running, or any aerobic training in moderation, has a positive effect on health. There is a point of diminishing returns, where chronic stress from overtraining, which is common in runners, may be linked to problems in the adrenal gland. Overtraining Syndrome (OS) has been linked with adrenal insufficiency. There is a direct link between stress and the adrenal glands, and the physical stress of overtraining may cause the hormones produced in these glands to become depleted. Overtraining Syndrome (OS) has been described as chronic fatigue, burnout and staleness, where an imbalance between training/competition, versus recovery occurs. Training alone is seldom the primary cause. In most cases, the total amount of stress on the athlete exceeds their capacity to cope. A triggering stressful event, along with the chronic overtraining, pushes the athlete to start developing symptoms of overtraining syndrome, which is far worse than classic overtraining. Overtraining can be a part of healthy training, if only done for a short period of time. Chronic overtraining is what leads to serious health problems, including adrenal insufficiency. Severe overtraining over an extended period can result in adrenal depletion. An Addison-Type overtraining syndrome, where the adrenal glands are no longer able to maintain proper hormone levels and athletic performance is severely compromised has been described by researchers. The purpose of this review is to describe the relationship between overtraining, chronic fatigue, and adrenal insufficiency and to address the overlap in these conditions, as well as examine critical research on the relationship between the dysfunction of the adrenal axis in over trained and stressed athletes.
44Exhaustion-related changes in cardiovascular and cortisol reactivity to acute psychosocial stress.PubMed
Peter Jönsson, Kai Österberg, Mattias Wallergård, et al.
Physiol Behav. 2015 Nov 1;151:327-37. doi: 10.1016/j.physbeh.2015.07.020. Epub 2015 Jul 22.
Prior findings indicate that individuals scoring high on vital exhaustion show a dysfunctional stress response (DSR), that is, reduced cortisol reactivity and habituation to psychosocial stressors. The main aim of the present study was to examine whether a DSR may be a vulnerability factor in exhaustion disorder (ED). We examined whether a DSR is present during the early stages of ED, and still is present after recovery. Three groups were studied: 1. Former ED patients (n=14); 2. persons who during the past 6 month had experienced stress at work and had a Shirom-Melamed Burnout Questionnaire (SMBQ) score over 3.75, considered to indicate a pre-stage of ED (n=17); 3. persons who had not experienced stress at work during the past 6 months and had a SMBQ score below 2.75 (n=20). The participants were exposed twice to a virtual version of the Trier Social Stress Test (V-TSST), during which salivary cortisol samples were collected. In addition, high frequency heart rate variability (HF-HRV), heart rate (HR), t-wave amplitude (TWA), and α-amylase were assessed to examine stress reactivity and habituation in the autonomic nervous system (ANS). The initial analyses showed clear hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activations in both V-TSST sessions, together with habituation of cortisol and heart rate in the second session, but without any significant group differences. However, the former ED patients showed considerable variation in self-reported signs of exhaustion (SMBQ). This led us to assign former ED patients with lower ratings into the low SMBQ group (LOWS) and those with higher ratings to the high SMBQ group (HIGHS). When repeating the analyses a different picture emerged; the HIGHS showed a lower cortisol response to the V-TSST than did the LOWS. Both groups' cortisol response habituated to the second V-TSST session. The ANS responses did not differ between the two groups. Thus, persons in a pre-stage of ED and unrecovered former ED patients showed signs of DSR, in contrast to healthy controls and recovered former ED patients. The results may be interpreted as indicating that DSR in the HPA axis is present early on in the stress process, but subsides after successful recovery.
45Psychosocial and biological predictors of resident physician burnout.PubMed
V Olivé, R Navinés, L Macías, et al.
Gen Hosp Psychiatry. 2022 Sep-Oct;78:68-71. doi: 10.1016/j.genhosppsych.2022.07.007. Epub 2022 Jul 22.
BACKGROUND: A high proportion of health professionals in training suffer from work-related stress and may develop a burnout syndrome. OBJECTIVES: To study the incidence of burnout after the first year of residency in a teaching hospital and to identify baseline psychological, psychosocial work conditions, and biological risk factors. METHODOLOGY: We assessed the following in a prospective cohort of residents at baseline (first month residence) and after 1 year: background factors (socio-demographics, psychiatric history), perceived stress score (Perceived Stress Scale), Maslach Burnout Inventory score, and psychosocial factors (Job Content Questionnaire). Blood samples were obtained to study serum cortisol, IL-6, and TNF-α concentrations. The cumulative incidence was modelled by multivariate log-binomial regression analysis. RESULTS: We included 71 participants with a female majority (64.8%), age 26.4 (2.65) years, psychiatric history in 20%, and burnout in 13%. Among those without burnout initially (N = 59), it had developed by 1 year in 22% of residents. Increased job demand (RR = 1.259, 95%CI = 1.019-1.556, p = 0.033) and decreased cortisol levels (RR = 0.877, 95%CI = 0.778-0.989, p = 0.032) predicted burnout after 1 year of residency among medical trainees. CONCLUSION: Burnout syndrome develops in 22% of residents by 1 year of training and can be predicted by increased work demands and decreased cortisol levels.
46The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome.PubMed
L J Crofford
Z Rheumatol. 1998;57 Suppl 2:67-71. doi: 10.1007/s003930050239.
HPA axis abnormalities in FM, CFS, and other stress-related disorders must be placed in a broad clinical context. We know that interventions providing symptomatic improvement in patients with FM and CFS can directly or indirectly affect the HPA axis. These interventions include exercise, tricyclic anti-depressants, and serotonin reuptake inhibitors. There is little direct information as to how the specific HPA axis perturbations seen in FM can be related to the major symptomatic manifestations of pain, fatigue, sleep disturbance, and psychological distress. Since many of these somatic and psychological symptoms are present in other syndromes that exhibit HPA axis disturbances, it seems reasonable to suggest that there may be some relationship between basal and dynamic function of the HPA axis and clinical manifestations of FM and CFS.
47Possible Development of Burn-Out Nonalcoholic Steatohepatitis under Long-Term Steroid Use.PubMed
Soichiro Ota, Michika Hamada, Ken-Ichi Muramatsu, et al.
Case Rep Gastroenterol. 2022 Sep 19;16(3):557-562. doi: 10.1159/000526570. eCollection 2022 Sep-Dec.
A 74-year-old man, who lived alone, was found in an unconscious state in his house by a neighbor after mail accumulated in his mailbox. He had asthma and nephrotic syndrome, which had been treated by prednisolone (10 mg) for more than 10 years, and steroid-induced DM. He had been obese since his 20s and had never drunk or smoked in his life. On arrival, he was obese and in a coma and shock state with respiratory failure. He therefore underwent rapid fluid resuscitation, tracheal intubation, mechanical ventilation, with cardiopressor treatment. Whole body computed tomography revealed atrophic liver and excess visceral fat. The clinical diagnosis was septic shock, acute respiratory failure, renal failure with hyperkalemia, cerebral ischemia, liver cirrhosis, rhabdomyolysis, DM, and upper gastrointestinal bleeding. On day 3, his circulation, respiratory function, and consciousness stabilized, and he was extubated. Further studies led to a diagnosis of burn-out nonalcoholic steatohepatitis (NASH). His condition was complicated by adrenal insufficiency, pulmonary embolism, lower extremity motor weakness, and left leg phlegmon during hospitalization. He was transferred to another hospital for rehabilitation on day 34 after the improvement of phlegmon. The present case showed the potential for NASH to develop in individuals with long-term steroid use. The further accumulation and analysis of cases is required to determine whether this possibility is correct or not.
48Elevated diurnal salivary cortisol in nurses is associated with burnout but not with vital exhaustion.PubMed
Katja Wingenfeld, Michael Schulz, Annika Damkroeger, et al.
Psychoneuroendocrinology. 2009 Sep;34(8):1144-51. doi: 10.1016/j.psyneuen.2009.02.015. Epub 2009 Mar 24.
Studies on HPA axis regulation in burnout revealed heterogeneous results, possibly due to different psychometric and endocrine measurements, heterogeneous samples or small sample sizes. In the present study, the relationship between salivary cortisol during the day (four time points: 0700 h, 1130 h, 1730 h, and 2000 h) and burnout as well as vital exhaustion was investigated in a large sample of 279 nurses. Burnout was measured using the Maslach Burnout Inventory (MBI), which includes scales for emotional exhaustion, depersonalization, and personal accomplishment. A burnout criterion was assumed to be fulfilled, when any of the MBI scales was above the norm. Subjects with two burnout criterions fulfilled (N=18) were characterized by a higher cortisol release over the day compared to those reporting only one criterion (N=77) or no burnout (N=181) (ANOVA, p=.015). On the other hand, subjects who reported high levels of vital exhaustion did not differ from those who did not report signs of vital exhaustion. These findings provide further evidence for HPA axis dysregulation in burnout.
49Stress and hair cortisol concentrations in nurses during the first wave of the COVID-19 pandemic.PubMed
Jakub Rajcani, Simona Vytykacova, Petra Solarikova, et al.
Psychoneuroendocrinology. 2021 Jul;129:105245. doi: 10.1016/j.psyneuen.2021.105245. Epub 2021 Apr 27.
During the COVID-19 pandemic, frontline healthcare workers have been exposed to very stressful conditions. Measuring hair cortisol concentrations (HCCs), which reflect the integrated long-term cortisol levels, may elucidate the impact of COVID-19 related stress on healthcare professionals. In the current study, we investigated experienced stress in 693 healthcare workers, with hair samples for cortisol analysis collected from a subset of 67 female nurses. The HCCs in two 3 cm hair segments corresponding to periods before and during the peak of the first wave of COVID-19 were compared. To evaluate the effect of working in the first line, the sample was divided into two groups based on the COVID-19 risk estimated by the nurses. Covariates in the model included perceived stress (PSS), perceived social support (MSPSS), and quality of sleep (PSQI) measured via an online questionnaire. The data showed that more than 75% of healthcare workers agreed that COVID-19 led to increased stress at their workplace. The hair cortisol analysis showed higher HCCs in the hair segments corresponding to the time of the pandemic compared to hair corresponding to an earlier period (partial η = 0.123-0.397); in the same model, higher HCCs were also found in nurses from high-risk environments compared to low-risk ones (partial η = 0.002-0.176). None of the subjective questionnaire measures were significant predictors of HCCs. In conclusion, these data showed that HCCs reflect the increased stress among nurses during the COVID-19 pandemic as well as the difference in nurses between high- and low-risk environments.
50The hypothalamo-pituitary-adrenal axis and the autonomic nervous system in burnout.PubMed
Anna Sjörs Dahlman, Ingibjörg H Jonsdottir, Caroline Hansson
Handb Clin Neurol. 2021;182:83-94. doi: 10.1016/B978-0-12-819973-2.00006-X.
Burnout constitutes a serious health concern in the modern working environment. It is a stress-related condition that has developed as a result of a prolonged psychosocial stress exposure causing a persistent mismatch between demands and resources. The main symptom is emotional exhaustion, but physical fatigue, diminished professional efficacy, cynicism, and cognitive impairments are also associated with this condition. Burnout has been used both as a psychologic term in occupational settings and as a clinical diagnosis in patient populations, and there is currently no universally accepted definition and diagnostic criteria of burnout. It has been hypothesized that the two main stress response systems, the autonomic nervous system (ANS) and the hypothalamus-pituitary-adrenal axis (HPA axis), are involved in the pathogenesis of burnout. A common hypothesis is that in the early stages of chronic stress, the HPA axis and sympathetic ANS activity tend to be higher, while it will decrease with a longer duration of chronic stress to ultimately reach a state of hypoactivity in clinical burnout. The current research in this field shows many contradictory results. Thus there is no compelling evidence of either ANS or HPA dysfunction in burnout. However, there is partial support for the hypothesis of HPA and sympathetic hyperactivity in early stages, and HPA hyporeactivity and low vagal activity in more severe burnout cases, but high-quality studies investigating the causal links are still lacking.
51Monitoring fitness, fatigue and running performance during a pre-season training camp in elite football players.PubMed
M Buchheit, S Racinais, J C Bilsborough, et al.
J Sci Med Sport. 2013 Nov;16(6):550-5. doi: 10.1016/j.jsams.2012.12.003. Epub 2013 Jan 14.
OBJECTIVES: To examine the usefulness of selected physiological and perceptual measures to monitor fitness, fatigue and running performance during a pre-season, 2-week training camp in eighteen professional Australian Rules Football players (21.9±2.0 years). DESIGN: Observational. METHODS: Training load, perceived ratings of wellness (e.g., fatigue, sleep quality) and salivary cortisol were collected daily. Submaximal exercise heart rate (HRex) and a vagal-related heart rate variability index (LnSD1) were also collected at the start of each training session. Yo-Yo Intermittent Recovery level 2 test (Yo-YoIR2, assessed pre-, mid- and post-camp, temperate conditions) and high-speed running distance during standardized drills (HSR, >14.4 km h(-1), 4 times throughout, outdoor) were used as performance measures. RESULTS: There were significant (P<0.001 for all) day-to-day variations in training load (coefficient of variation, CV: 66%), wellness measures (6-18%), HRex (3.3%), LnSD1 (19.0%), but not cortisol (20.0%, P=0.60). While the overall wellness (+0.06, 90% CL (-0.14; 0.02) AU day(-1)) did not change substantially throughout the camp, HRex decreased (-0.51 (-0.58; -0.45)% day(-1)), and cortisol (+0.31 (0.06; 0.57) nmol L(-1)day(-1)), LnSD1 (+0.1 (0.04; 0.06) ms day(-1)), Yo-YoIR2 performance (+23.7 (20.8; 26.6) m day(-1), P<0.001), and HSR (+4.1 (1.5; 6.6) m day(-1), P<0.001) increased. Day-to-day ΔHRex (r=0.80, 90% CL (0.75; 0.85)), ΔLnSD1 (0.51 (r=0.40; 0.62)) and all wellness measures (0.28 (-0.39; -0.17)<r<0.25 (0.14; 0.36)) were related to Δtraining load. There was however no clear relationship between Δcortisol and Δtraining load. ΔYo-YoIR2 was correlated with ΔHRex (r=0.88 (0.84; 0.92)), ΔLnSD1 (r=0.78 (0.67; 0.89)), Δwellness (r=0.58 (0.41; 0.75), but not Δcortisol. ΔHSR was correlated with ΔHRex (r = -0.27 (-0.48; -0.06)) and Δwellness (r=0.65 (0.49; 0.81)), but neither with ΔLnSD1 nor Δcortisol. CONCLUSIONS: Training load, HRex and wellness measures are the best simple measures for monitoring training responses to an intensified training camp; cortisol post-exercise and LnSD1 did not show practical efficacy here.
52Training, psychometric status, biological markers and neuromuscular fatigue in soccer.PubMed
Okba Selmi, Ibrahim Ouergui, Danielle E Levitt, et al.
Biol Sport. 2022 Mar;39(2):319-327. doi: 10.5114/biolsport.2022.104065. Epub 2021 Apr 9.
The study examined the relationship between psychometric status, neuromuscular, and biochemical markers of fatigue in response to an intensified training (IT) period in soccer. Fifteen professional soccer players volunteered to participate in the study (mean ± SD: age: 25 ± 1 years; body height: 179 ± 7 cm, body mass: 73.7 ± 16.2 kg, experience: 13.2 ± 3 years). Training load, monotony, strain, Hooper index and total quality recovery (TQR) were determined for each training session during a 2-week of IT. Counter-movement jump (CMJ) and biochemical responses [testosterone, cortisol, testosterone-to-cortisol ratio (T/C ratio), creatine kinase, and C-reactive protein] were collected before and after IT. Results showed that IT induced significant increases in cortisol, creatine kinase and C-reactive protein and significant decreases in T/C ratio and CMJ performance from before to after IT (p < 0.01, p < 0.001, p < 0.001, p < 0.01, p < 0.05, respectively). However, testosterone did not differ from before to after IT (p > 0.05). Training loads were positively correlated with Hooper index (p < 0.05) and negatively correlated with total quality recovery (p < 0.05). Hooper index was positively correlated with cortisol (p < 0.05), T/C ratio (p < 0.01), and creatine kinase (p < 0.01), and negatively correlated with CMJ (p < 0.05). Furthermore, TQR was negatively correlated with T/C ratio (p < 0.01), creatine kinase (p < 0.001), and C-reactive protein (p < 0.05), and positively correlated with CMJ (p < 0.01). Neuromuscular fatigue, muscle damage, and change in the anabolic/catabolic state induced by the IT were related to well-being and perceived recovery state among professional soccer players.
53Salivary Cortisol Analysis in Collegiate Female Lacrosse Athletes.PubMed
Jenna Carter, Stephanie L Mathews, Yvette L Figueroa, et al.
Int J Exerc Sci. 2023 Feb 1;16(6):242-251. doi: 10.70252/DZSA8083. eCollection 2023.
Cortisol is a hormone that corresponds to physiological and emotional stress. The purpose of this study was to 1) evaluate the changes in cortisol in female Division I collegiate lacrosse players ( = 15) throughout the competitive season, and 2) evaluate the correlation between cortisol and athlete wellness and workload. Salivary cortisol samples were collected weekly in the morning throughout the entirety of the 2021 competitive season (12 weeks). Subjective athlete total wellness scores and sub-scores (muscle soreness, sleep quality, fatigue, and stress) were taken on the same days. Objective total weekly Athlete Load (AL, an amalgam workload metric) were tabulated from the previous training week. A significant effect of time was found on wellness ( < 0.001) and AL ( < 0.001) over the twelve weeks with weekly differences, such as weeks with more than one game, weeks with no games, weeks with students in quarantine (not competing), or weeks with academic stressors such as final exams. There were no weekly differences in cortisol ( = 0.058). Cortisol had negligible correlations with wellness ( = -0.010, = 0.889) and AL ( = 0.083, = 0.272) during the competitive season. These findings suggest that cortisol changed little for athletes throughout the season although training volume and wellness did. Thus, assessing acute responses of cortisol may prove to be more beneficial to evaluating athletes' stress.
54Effect of the intake of high or low glycemic index high carbohydrate-meals on athletes' sleep quality in pre-game nights.PubMed
Natália V S Daniel, Ioná Z Zimberg, Debora Estadella, et al.
An Acad Bras Cienc. 2019;91(1):e20180107. doi: 10.1590/0001-3765201920180107. Epub 2019 Apr 8.
This study investigated the effect of the intake of high (HGI) or low glycemic index (LGI) high-carbohydrate meals on athletes' sleep. Nine basketball adult male athletes were assessed during a championship and received high-carbohydrate meals (dinner and evening snack) with HGI or LGI. Quantitative and qualitative sleep variables were assessed: sleep latency (LAT), sleep efficiency (EFIC), Wake After Sleep Onset (WASO), sleep time through actigraphy and sleep diary. Dietary intake, satiety, sleepiness, glycemic response, salivary cortisol and melatonin were also assessed. On both days most athletes had LAT and WASO higher than recommendation, and nocturnal sleep time below the recommendations. There was no difference between sleep and hormonal parameters according to GI dietary manipulations; however, correlations were observed between sleep and diet. Daily energy intake had negative correlation with efficiency and nocturnal total sleep time, and a positive correlation with WASO, regardless of the GI nocturnal meals. No differences were observed in salivary cortisol and melatonin according to GI. The results suggest that food intake throughout the day seems to exert more influence on sleep parameters of basketball players than GI manipulation of evening meals on the pre-night game, but further studies are necessary to better understand this complex relationship.
55Effects of forest therapy on salivary biomarkers (cortisol, amylase and IGA) in pediatric cáncer survivors: an experimental study.PubMed
Francisco Díaz-Martínez, Miguel Felipe Sánchez-Sauco, Esteban Orenes-Piñero, et al.
An Pediatr (Engl Ed). 2023 Nov;99(5):356-357. doi: 10.1016/j.anpede.2023.10.007. Epub 2023 Oct 26.
56Sustained Sleep Restriction Reduces Resistance Exercise Quality and Quantity in Females.PubMed
Olivia E Knowles, Eric J Drinkwater, Spencer S H Roberts, et al.
Med Sci Sports Exerc. 2022 Dec 1;54(12):2167-2177. doi: 10.1249/MSS.0000000000003000. Epub 2022 Sep 22.
INTRODUCTION: Female athletes sleep less and report more sleep problems than their male counterparts. Inadequate sleep reduces maximal strength in male athletes; however, little is known about the impact of sleep restriction (SR) on the quantity and quality of resistance exercise performed by female athletes. This study investigated the effect of nine nights of moderate SR on repeated resistance exercise performance, hormonal responses, and perceived fatigue in females. METHODS: Ten healthy, resistance-trained, eumenorrheic females age 18-35 yr underwent nine nights of SR (5-h time in bed) and normal sleep (NS; ≥7-h time in bed) in a randomized, crossover fashion with a minimum 6-wk washout. Participants completed four resistance exercise sessions per trial, with blood samples collected before and after exercise. Exercise performance was assessed using volume load, reactive strength index, and mean concentric velocity with rating of perceived exertion recorded after exercise. Participants completed awakening saliva sampling and the Multi-component Training Distress Scale daily. RESULTS: Volume load decreased trivially (<1%, P < 0.05) with SR. Mean concentric velocity per set was slower during SR for the lower-body (up to 15%, P < 0.05), but not the upper-body, compound lifts. Intraset velocity loss was up to 7% greater during SR for back squats ( P < 0.05). SR increased salivary cortisol area under the curve (by 42%), total training distress (by 84%), and session perceived exertion (by 11%). CONCLUSIONS: Sustained SR reduces markers of resistance exercise quality (bar velocity) more than quantity (volume load) and increases perceived effort at the same relative intensity in resistance-trained females. Markers of exercise quality and internal load may be more sensitive than volume load, to advise coaches to the decline in lifting performance for female athletes experiencing SR.
57Dynamics of Physiological, Biochemical and Psychological Markers during Single Session of Virtual Reality-Based Respiratory Biofeedback Relaxation.PubMed
Eglė Mazgelytė, Julija Zagorskaja, Edita Dereškevičiūtė, et al.
Behav Sci (Basel). 2022 Nov 28;12(12):482. doi: 10.3390/bs12120482.
Psychological stress exposure is associated with long-lasting health effects including memory problems, depression, aches and pains, eating disorders, and alcohol or drug use. Thus, there is a need to develop effective stress management strategies that are easy to learn and practice. Respiratory biofeedback is an evidence-based stress management technique presenting breathing-related information to help subjects learn specific breathing skills for relaxation. It is suggested that the use of biofeedback techniques in conjunction with virtual reality makes biofeedback training an even more effective tool for stress management. The current study aimed to investigate dynamics of distinct stress indicators before, after, as well as during one brief virtual reality-based respiratory biofeedback session. Thirty-nine healthy volunteers participated in the study. Individuals provided their saliva samples and evaluated their mood status, fatigue, and strain level before and after the session. The subjects' heart and respiratory rate, heart rate variability, and galvanic skin response measures were recorded during the session. The results showed that after single 12 min relaxation session, there was a significant decrease in salivary cortisol concentration, heart and respiratory rate, as well as decrease in skin conductance values. Self-reported strain, fatigue level, and mood status also significantly improved. VR-based respiratory-biofeedback-assisted relaxation sessions might serve as an effective stress management strategy, as even single session had positive effects on subjects' autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis activity, as well as self-reported fatigue, strain level, and mood status.
58Natural product HTP screening for antibacterial (E.coli 0157:H7) and anti-inflammatory agents in (LPS from E. coli O111:B4) activated macrophages and microglial cells; focus on sepsis.PubMed
Elizabeth A Mazzio, Nan Li, David Bauer, et al.
BMC Complement Altern Med. 2016 Nov 15;16(1):467. doi: 10.1186/s12906-016-1429-x.
BACKGROUND: Acute systemic inflammatory response syndrome arising from infection can lead to multiple organ failure and death, with greater susceptibility occurring in immunocompromised individuals. Moreover, sub-acute chronic inflammation is a contributor to the pathology of diverse degenerative diseases (Parkinson's disease, Alzheimer's disease and arthritis). Given the known limitations in Western medicine to treat a broad range of inflammatory related illness as well as the emergence of antibiotic resistance, there is a renewed interest in complementary and alternative medicines (CAMs) to achieve these means. METHODS: A high throughput (HTP) screening of >1400 commonly sold natural products (bulk herbs, cooking spices, teas, leaves, supplement components, nutraceutical food components, fruit and vegetables, rinds, seeds, polyphenolics etc.) was conducted to elucidate anti-inflammatory substances in lipopolysaccharide (LPS) (E. coli serotype O111:B4) monocytes: RAW 264.7 macrophages [peripheral], BV-2 microglia [brain]) relative to hydrocortisone, dexamethasone and L-N6-(1Iminoethyl)lysine (L-NIL). HTP evaluation was also carried out for lethal kill curves against E.coli 0157:H7 1x10 CFU/mL relative to penicillin. Validation studies were performed to assess cytokine profiling using antibody arrays. Findings were corroborated by independent ELISAs and NO2-/iNOS expression quantified using the Griess Reagent and immunocytochemistry, respectively. For robust screening, we developed an in-vitro efficacy paradigm to ensure anti-inflammatory parameters were observed independent of cytotoxicity. This caution was taken given that many plants exert tumoricidal and anti-inflammatory effects at close range through similar signaling pathways, which could lead to false positives. RESULTS: The data show that activated BV-2 microglia cells (+ LPS 1μg/ml) release >10-fold greater IL-6, MIP1/2, RANTES and nitric oxide (NO2-), where RAW 264.7 macrophages (+ LPS 1μg/ml) produced > 10-fold rise in sTNFR2, MCP-1, IL-6, GCSF, RANTES and NO2-. Data validation studies establish hydrocortisone and dexamethasone as suppressing multiple pro-inflammatory processes, where L-NIL suppressed NO2-, but had no effect on iNOS expression or IL-6. The screening results demonstrate relative few valid hits with anti-inflammatory effects at < 250μg/ml for the following: Bay Leaf (Laurus nobilis), Elecampagne Root (Inula helenium), Tansy (Tanacetum vulgare),Yerba (Eriodictyon californicum) and Centipeda (Centipeda minima), Ashwagandha (Withania somnifera), Feverfew (Tanacetum parthenium), Rosemary (Rosmarinus officinalis), Turmeric Root (Curcuma Longa), Osha Root (Ligusticum porteri), Green Tea (Camellia sinensis) and constituents: cardamonin, apigenin, quercetin, biochanin A, eupatorin, (-)-epigallocatechin gallate (EGCG) and butein. Natural products lethal against [E. coli 0157:H7] where the LC < 100 μg/ml included bioactive silver hydrosol-Argentyn 23, green tea (its constituents EGCG > Polyphenon 60 > (-)-Gallocatechin > Epicatechin > (+)-Catechin), Grapeseed Extract (Vitis vinifera), Chinese Gallnut (its constituents gallic acid > caffeic acid) and gallic acid containing plants such as Babul Chall Bark (Acacia Arabica), Arjun (Terminalia Arjuna) and Bayberry Root Bark (Morella Cerifera). CONCLUSIONS: These findings emphasize and validate the previous work of others and identify the most effective CAM anti-inflammatory, antibacterial compounds using these models. Future work will be required to evaluate potential combination strategies for long-term use to prevent chronic inflammation and possibly lower the risk of sepsis in immunocompromised at risk populations.
59Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2- in LPS/IFNγ activated glioma cells.PubMed
Elizabeth A Mazzio, David Bauer, Patricia Mendonca, et al.
J Neuroimmunol. 2017 Jan 15;302:10-19. doi: 10.1016/j.jneuroim.2016.11.012. Epub 2016 Dec 1.
Chronic and acute central nervous system (CNS) inflammation are contributors toward neurological injury associated with head trauma, stroke, infection, Parkinsons or Alzheimers disease. CNS inflammatory illnesses can also contribute toward risk of developing glioblastoma multiforme (GBM). With growing public interest in complementary and alternative medicines (CAMs), we conduct a high throughput (HTP) screening of >1400 natural herbs, plants and over the counter (OTC) products for anti-inflammatory effects on lipopolysaccharide (LPS)/interferon gamma (IFNγ) activated C6 glioma cells. Validation studies were performed showing a pro-inflammatory profile of [LPS 3 µg/ml/ IFNγ 3 ng/ml] consistent with greater release [>8.5 fold] of MCP-1, NO2-, cytokine-induced neutrophil chemo-attractants (CINC) 1, CINC 2a and CINC3. The data show no changes to the following, IL-13, TNF-a, fracktaline, leptin, LIX, GM-CSF, ICAM1, L-Selectin, activin A, agrin, IL-1α, MIP-3a, B72/CD86, NGF, IL-1b, MMP-8, IL-1 R6, PDGF-AA, IL-2, IL-4, prolactin R, RAGE, IL-6, Thymus Chemokine-1, CNTF,IL-10 or TIMP-1. A HTP screening was conducted, where we employ an in vitro efficacy index (iEI) defined as the ratio of toxicity (LC)/anti-inflammatory potency (IC). The iEI was precautionary to ensure biological effects were occurring in fully viable cells (ratio > 3.8) independent of toxicity. Using NO2- as a guideline molecule, the data show that 1.77% (25 of 1410 tested) had anti-inflammatory effects with iEI ratios >3.8 and ICs <250µg/ml. These include reference drugs (hydrocortisone, dexamethasone N6-(1-iminoethyl)-l-lysine and NSAIDS: diclofenac, tolfenamic acid), a histone deacetylase inhibitor (apicidin) and the following natural products; Ashwaganda (Withania somnifera), Elecampagne Root (Inula helenium), Feverfew (Tanacetum parthenium), Green Tea (Camellia sinensis), Turmeric Root (Curcuma longa) Ganthoda (Valeriana wallichii), Tansy (Tanacetum vulgare), Maddar Root (Rubia tinctoria), Red Sandle wood (Pterocarpus santalinus), Bay Leaf (Laurus nobilis, Lauraceae), quercetin, cardamonin, fisetin, EGCG, biochanin A, galangin, apigenin and curcumin. The herb with the largest iEI was Ashwaganda where the IC/LC was 11.1/>1750.0μg/ml, and the compound with the greatest iEI was quercetin where the IC/LC was 10.0/>363.6μg/ml. These substances also downregulate the production of iNOS expression and attenuate CINC-3 release. In summary, this HTP screening provides guideline information about the efficacy of natural products that could prevent inflammatory processes associated with neurodegenerative disease and aggressive glioma tumor growth.
60Chronic inflammation in post-acute sequelae of COVID-19 modulates gut microbiome: a review of literature on COVID-19 sequelae and gut dysbiosis.PubMed
Najeeha Talat Iqbal, Hana Khan, Aqsa Khalid, et al.
Mol Med. 2025 Jan 23;31(1):22. doi: 10.1186/s10020-024-00986-6.
BACKGROUND: Long COVID or Post-acute sequelae of COVID-19 is an emerging syndrome, recognized in COVID-19 patients who suffer from mild to severe illness and do not recover completely. Most studies define Long COVID, through symptoms like fatigue, brain fog, joint pain, and headache prevailing four or more weeks post-initial infection. Global variations in Long COVID presentation and symptoms make it challenging to standardize features of Long COVID. Long COVID appears to be accompanied by an auto-immune multi-faceted syndrome where the virus or viral antigen persistence causes continuous stimulation of the immune response, resulting in multi-organ immune dysregulation. MAIN TEXT: This review is focused on understanding the risk factors of Long COVID with a special emphasis on the dysregulation of the gut-brain axis. Two proposed mechanisms are discussed here. The first mechanism is related to the dysfunction of angiotensin-converting enzyme 2 receptor due to Severe Acute Respiratory Syndrome Corona Virus 2 infection, leading to impaired mTOR pathway activation, reduced AMP secretion, and causing dysbiotic changes in the gut. Secondly, gut-brain axis dysregulation accompanied by decreased production of short-chain fatty acids, impaired enteroendocrine cell function, and increased leakiness of the gut, which favors translocation of pathogens or lipopolysaccharide in circulation causing the release of pro-inflammatory cytokines. The altered Hypothalamic-Pituitary-Adrenal axis is accompanied by the reduced level of neurotransmitter, and decreased stimulation of the vagus nerve, which may cause neuroinflammation and dysregulation of serum cortisol levels. The dysbiotic microbiome in Long COVID patients is characterized by a decrease in beneficial short chain fatty acid-producing bacteria (Faecalibacterium, Ruminococcus, Dorea, and Bifidobacterium) and an increase in opportunistic bacteria (Corynebacterium, Streptococcus, Enterococcus). This dysbiosis is transient and may be impacted by interventions including probiotics, and dietary supplements. CONCLUSIONS: Further studies are required to understand the geographic variation, racial and ethnic differences in phenotypes of Long COVID, the influence of viral strains on existing and emerging phenotypes, to explore long-term effects of gut dysbiosis, and gut-brain axis dysregulation, as well as the potential role of diet and probiotics in alleviating those symptoms.
61Effect of Soy Protein Supplementation on Muscle Adaptations, Metabolic and Antioxidant Status, Hormonal Response, and Exercise Performance of Active Individuals and Athletes: A Systematic Review of Randomised Controlled Trials.PubMed
Reza Zare, Asli Devrim-Lanpir, Silvia Guazzotti, et al.
Sports Med. 2023 Dec;53(12):2417-2446. doi: 10.1007/s40279-023-01899-w. Epub 2023 Aug 21.
BACKGROUND: Protein supplements are important to maintain optimum health and physical performance, particularly in athletes and active individuals to repair and rebuild their skeletal muscles and connective tissues. Soy protein (SP) has gained popularity in recent years as an alternative to animal proteins. OBJECTIVES: This systematic review evaluates the evidence from randomised controlled clinical trials of the effects of SP supplementation in active individuals and athletes in terms of muscle adaptations, metabolic and antioxidant status, hormonal response and exercise performance. It also explores the differences in SP supplementation effects in comparison to whey protein. METHODS: A systematic search was conducted in PubMed, Embase and Web of Science, as well as a manual search in Google Scholar and EBSCO, on 27 June 2023. Randomised controlled trials that evaluated the applications of SPs supplementation on sports and athletic-related outcomes that are linked with exercise performance, adaptations and biomarkers in athletes and physically active adolescents and young adults (14 to 39 years old) were included, otherwise, studies were excluded. The risk of bias was assessed according to Cochrane's revised risk of bias tool. RESULTS: A total of 19 eligible original research articles were included that investigated the effect of SP supplementation on muscle adaptations (n = 9), metabolic and antioxidant status (n = 6), hormonal response (n = 6) and exercise performance (n = 6). Some studies investigated more than one effect. SP was found to provide identical increases in lean mass compared to whey in some studies. SP consumption promoted the reduction of exercise-induced metabolic/blood circulating biomarkers such as triglycerides, uric acid and lactate. Better antioxidant capacity against oxidative stress has been seen with respect to whey protein in long-term studies. Some studies reported testosterone and cortisol fluctuations related to SP; however, more research is required. All studies on SP and endurance performance suggested the potential beneficial effects of SP supplementation (10-53.3 g) on exercise performance by improving high-intensity and high-speed running performance, enhancing maximal cardiac output, delaying fatigue and improving isometric muscle strength, improving endurance in recreational cyclists, increasing running velocity and decreasing accumulated lactate levels; however, studies determining the efficacy of soy protein on VOmax provided conflicted results. CONCLUSION: It is possible to recommend SP to athletes and active individuals in place of conventional protein supplements by assessing their dosage and effectiveness in relation to different types of training. SP may enhance lean mass compared with other protein sources, enhance the antioxidant status, and reduce oxidative stress. SP supplementation had an inconsistent effect on testosterone and cortisol levels. SP supplementation may be beneficial, especially after muscle damage, high-intensity/high-speed or repeated bouts of strenuous exercise.
62Adrenal insufficiency.PubMed
Stefanie Hahner, Richard J Ross, Wiebke Arlt, et al.
Nat Rev Dis Primers. 2021 Mar 11;7(1):19. doi: 10.1038/s41572-021-00252-7.
Adrenal insufficiency (AI) is a condition characterized by an absolute or relative deficiency of adrenal cortisol production. Primary AI (PAI) is rare and is caused by direct adrenal failure. Secondary AI (SAI) is more frequent and is caused by diseases affecting the pituitary, whereas in tertiary AI (TAI), the hypothalamus is affected. The most prevalent form is TAI owing to exogenous glucocorticoid use. Symptoms of AI are non-specific, often overlooked or misdiagnosed, and are related to the lack of cortisol, adrenal androgen precursors and aldosterone (especially in PAI). Diagnosis is based on measurement of the adrenal corticosteroid hormones, their regulatory peptide hormones and stimulation tests. The goal of therapy is to establish a hormone replacement regimen that closely mimics the physiological diurnal cortisol secretion pattern, tailored to the patient's daily needs. This Primer provides insights into the epidemiology, mechanisms and management of AI during pregnancy as well as challenges of long-term management. In addition, the importance of identifying life-threatening adrenal emergencies (acute AI and adrenal crisis) is highlighted and strategies for prevention, which include patient education, glucocorticoid emergency cards and injection kits, are described.
63Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis.PubMed
Hanna Nowotny, S Faisal Ahmed, Sophie Bensing, et al.
Endocrine. 2021 Mar;71(3):586-594. doi: 10.1007/s12020-021-02649-6. Epub 2021 Mar 4.
Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20-50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives.
64Glucocorticoid replacement therapy for primary and secondary adrenal insufficiency and their impact on cognition.PubMed
Birgit Harbeck, Peter Kropp, Ilonka Kreitschmann-Andermahr
Front Endocrinol (Lausanne). 2023 Mar 17;14:1153595. doi: 10.3389/fendo.2023.1153595. eCollection 2023.
Patients with adrenal insufficiency (AI) are treated with conventional or modified-release glucocorticoid (GC) replacement therapy (GRT). Although current GRT regimens aim to mimic the physiological circadian pattern of cortisol secretion, temporary phases of hypo- and hypercortisolism are common. There is good evidence that prolonged phases of hypo- or hypercortisolism are associated with impaired cognitive functioning. However, little is known about cognitive functioning in patients with AI regarding the effects of dosage and duration of glucocorticoid replacement therapy. There is also little data available comparing the effects of GC therapy on patients with primary and secondary forms of AI as well as with respect to different formulas. This Mini-Review gives an overview of the current studies on GRT for primary and secondary AI and their impact on cognition. Strengths and weaknesses of the studies and their Implications for clinical daily routine are discussed with a special emphasis on practical considerations for the treating endocrinologist.
65Antibody-Coated Wearable Organic Electrochemical Transistors for Cortisol Detection in Human Sweat.PubMed
Silvia Demuru, Jaemin Kim, Marwan El Chazli, et al.
ACS Sens. 2022 Sep 23;7(9):2721-2731. doi: 10.1021/acssensors.2c01250. Epub 2022 Sep 2.
The dysregulation of the hormone cortisol is related to several pathological states, and its monitoring could help prevent severe stress, fatigue, and mental diseases. While wearable antibody-based biosensors could allow real-time and simple monitoring of antigens, an accurate and low-cost antibody-based cortisol detection through electrochemical methods is considerably challenging due to its low concentration and the high ionic strength of real biofluids. Here, a label-free and fast sensor for cortisol detection is proposed based on antibody-coated organic electrochemical transistors. The developed devices show unprecedented high sensitivities of 50 μA/dec for cortisol sensing in high-ionic-strength solutions with effective cortisol detection demonstrated with real human sweat. The sensing mechanism is analyzed through impedance spectroscopy and confirmed with electrical models. Compared to existing methods requiring bulky and expensive laboratory equipment, these wearable devices enable point-of-care cortisol detection in 5 min with direct sweat collection for personalized well-being monitoring.
66Evaluation of sweat-based biomarkers using wearable biosensors for monitoring stress and fatigue: a systematic review.PubMed
Jie Ma, Heng Li, Shahnawaz Anwer, et al.
Int J Occup Saf Ergon. 2024 Sep;30(3):677-703. doi: 10.1080/10803548.2024.2330242. Epub 2024 Apr 6.
. This systematic review aims to report the evaluation of wearable biosensors for the real-time measurement of stress and fatigue using sweat biomarkers. . A thorough search of the literature was carried out in databases such as PubMed, Web of Science and IEEE. A three-step approach for selecting research articles was developed and implemented. . Based on a systematic search, a total of 17 articles were included in this review. Lactate, cortisol, glucose and electrolytes were identified as sweat biomarkers. Sweat-based biomarkers are frequently monitored in real time using potentiometric and amperometric biosensors. Wearable biosensors such as an epidermal patch or a sweatband have been widely validated in scientific literature. . Sweat is an important biofluid for monitoring general health, including stress and fatigue. It is becoming increasingly common to use biosensors that can measure a wide range of sweat biomarkers to detect fatigue during high-intensity work. Even though wearable biosensors have been validated for monitoring various sweat biomarkers, such biomarkers can only be used to assess stress and fatigue indirectly. In general, this study may serve as a driving force for academics and practitioners to broaden the use of wearable biosensors for the real-time assessment of stress and fatigue.
67Pseudo-endocrine Disorders: Recognition, Management, and Action.PubMed
Michael T McDermott
J Endocr Soc. 2024 Dec 17;9(1):bvae226. doi: 10.1210/jendso/bvae226. eCollection 2024 Nov 26.
"Pseudo-endocrine disorders" refer to proposed conditions that have never been scientifically proven to exist but, due to widespread misinformation available on the internet and other media, are relatively commonly diagnosed and treated with equally unproven and sometimes dangerous treatments. Adrenal fatigue is a nonexistent condition that supposedly results from adrenal exhaustion and atrophy due to chronic stress and has been promoted as a potential explanation for a variety of symptoms. Testing consists of nonvalidated online surveys and salivary cortisol profiles while treatment is not evidence-based at best and can be dangerous. Wilson's syndrome and reverse T3 syndrome are also nonexistent conditions that supposedly result from impaired T4 to T3 conversion and competition of excess reverse T3 with T3 for T3 receptors. Testing involves measurement of axillary temperature and treatment consists of T3 therapy, often at very high and dangerous doses. Hypogonadism ("low T") is frequently diagnosed in "men's health" clinics and other venues without actual hormone testing or further evaluation and is often treated with supraphysiologic testosterone therapy that suppresses endogenous gonadal testosterone and sperm production, leads to a lifelong need for testosterone therapy, and may have numerous other harmful effects. Low-dose naltrexone (LDN) therapy has been proposed as a treatment for multiple disorders including autoimmune conditions and other disorders resulting from aberrant immune mechanisms, but there is no valid evidence that LDN has any benefits. Management of patients with pseudo-endocrine disorders must involve careful listening, patient education, healthy lifestyle measures, and honesty, encouragement, and compassion.
68Measurement of salivary cortisol in 2012 - laboratory techniques and clinical indications.PubMed
Warrick J Inder, Goce Dimeski, Anthony Russell
Clin Endocrinol (Oxf). 2012 Nov;77(5):645-51. doi: 10.1111/j.1365-2265.2012.04508.x.
The utility of measuring salivary cortisol has become increasingly appreciated since the early 1980s. Salivary cortisol is a measure of active free cortisol and follows the diurnal rhythm of serum or plasma cortisol. The saliva sample may be collected by drooling or through the use of absorbent swabs which are placed into the mouth until saturated. Salivary cortisol is therefore convenient for patients and research participants to collect noninvasively on an outpatient basis. Several assay techniques have been used to measure salivary cortisol, including radioimmunoassay and more recently liquid chromatography-tandem mass spectrometry. The analytical sensitivity varies between these assay methods, as does the potential for cross-reactivity with other steroids. The interpretation of salivary cortisol levels relies on rigorous standardization of sampling equipment, sampling protocols and assay technology with establishment of a local reference range. Clinically, the commonest use for salivary cortisol is measuring late-night salivary cortisol as a screening test for Cushing's syndrome. Several studies have shown diagnostic sensitivities and specificities of over 90%, which compares very favourably with other screening tests for Cushing's syndrome such as the 24-h urinary-free cortisol and the 1-mg overnight dexamethasone suppression test. There are emerging roles for the use of salivary cortisol in diagnosing adrenal insufficiency, particularly in conditions associated with low cortisol-binding globulin levels, and in the monitoring of glucocorticoid replacement. Finally, salivary cortisol has been used extensively as a biomarker of stress in a research setting, especially in studies examining psychological stress with repeated measurements.
69[Concept and clinical significance of subclinical Cushing syndrome].PubMed
Mitsuhide Naruse, Akiyo Tanabe, Mika Tsuiki
Rinsho Byori. 2010 Mar;58(3):232-7.
The clinical significance of subclinical Cushing syndrome has been widely recognized because of its high prevalence in adrenal incidentaloma. Circulatory and metabolic disorders are the most frequent and important complications of the disease state. Since those complications show aggravation during the clinical course and improvement after surgery, appropriate diagnosis and treatment are essential. Diagnostic criteria, especially the cutoff value of plasma cortisol after dexamethasone suppression, are markedly affected by the sensitivity and specificity of cortisol assay methods. Revision of the diagnostic criteria should reflect the prognosis of the disease state.
70Rates of adrenal insufficiency using a monoclonal vs. polyclonal cortisol assay.PubMed
Kyle P McNerney, Ana Maria Arbeláez
J Pediatr Endocrinol Metab. 2021 Dec 13;35(3):313-317. doi: 10.1515/jpem-2021-0519. Print 2022 Mar 28.
OBJECTIVES: The diagnosis of adrenal insufficiency relies on clear cut-offs and accurate measurement of cortisol levels. Newer monoclonal antibody assays may increase the rate of diagnosis of adrenal insufficiency if traditional cortisol cut-off levels <18 mcg/dL (500 nmol/L) are applied. We aimed to determine if the rate of diagnosis of adrenal insufficiency using a 1 mcg Cosyntropin stimulation test varied with the change in cortisol assay from a polyclonal to a monoclonal antibody assay. METHODS: Cortisol levels obtained during the 1 mcg Cosyntropin stimulation test performed in the last semester of 2016 using a polyclonal antibody cortisol assay were compared to tests performed using a monoclonal antibody cortisol assay during the first semester of 2017. Cosyntropin tests included cortisol values obtained at baseline, 20 min and 30 min after IV administration of 1 mcg Cosyntropin. Peak cortisol cut-off value <18 mcg/dL was used to diagnose adrenal insufficiency. RESULTS: Stimulated cortisol values after 1 mcg Cosyntropin using the monoclonal assay in 2017 (n=38) were significantly lower (33%) compared to those obtained with the polyclonal assay in 2016 (n=27) (p-value <0.001). The number of passing tests with a peak cortisol value >18 mcg/dL fell from 74% in 2016 (20 out of 27 tests) to 29% in 2017 (11 out of 38 tests). CONCLUSIONS: The change in cortisol assay substantially increased the number of patients diagnosed with adrenal insufficiency after 1 mcg Cosyntropin stimulation testing. Standardization of cortisol assays and diagnostic criteria is critical for the accurate diagnosis of adrenal insufficiency.
71Serum Cortisol: An Up-To-Date Assessment of Routine Assay Performance.PubMed
James M Hawley, Laura J Owen, Stephen J Lockhart, et al.
Clin Chem. 2016 Sep;62(9):1220-9. doi: 10.1373/clinchem.2016.255034. Epub 2016 Jul 20.
BACKGROUND: Accurate serum cortisol quantification is required for the correct diagnosis and management of adrenal pathologies. Presently, most laboratories use immunoassay to measure serum cortisol with proficiency schemes demonstrating a wide dispersion of results. Here, we investigate the effects of sex, matrix, and antibody specificity on serum cortisol quantification in 6 routine assays. METHODS: Surplus serum was obtained before disposal and the following cohorts were created: males, nonpregnant females, pregnant patients, and patients prescribed either metyrapone or prednisolone. Samples were anonymized and distributed to collaborating laboratories for cortisol analysis by 6 routine assays. Cortisol was also measured in all samples using an LC-MS/MS candidate reference measurement procedure (cRMP); cortisol-binding globulin (CBG) was measured in the nonpregnant and pregnant female cohorts. RESULTS: Considerable inter- and intraassay variation was observed across the male and nonpregnant female cohorts relative to the cRMP. Four immunoassays underrecovered cortisol in the pregnancy cohort, and CBG was found to be significantly higher in this cohort than in the nonpregnant females. In the metyrapone and prednisolone cohorts, all immunoassays overestimated cortisol. The first generation Roche E170 and Siemens Centaur XP were particularly prone to overestimation. In all cohorts the routine LC-MS/MS assay aligned extremely well with the cRMP. CONCLUSIONS: Despite the clinical importance of serum cortisol, the performance of routine immunoassays remains highly variable. Accurate quantification is compromised by both matrix effects and antibody specificity. Underpinning this study with a cRMP has highlighted the deficiencies in standardization across routine cortisol immunoassays.
72Usefulness of salivary cortisol in the diagnosis of hypercortisolism: comparison with serum and urinary cortisol.PubMed
Luca Manetti, Giuseppe Rossi, Lucia Grasso, et al.
Eur J Endocrinol. 2013 Feb 15;168(3):315-21. doi: 10.1530/EJE-12-0685. Print 2013 Mar.
OBJECTIVE: Several tests have been proposed to diagnose patients with Cushing's syndrome (CS). The aims of the study were: i) to evaluate the performance of salivary cortisol (SC) in hypercortisolism and ii) to compare SC with serum cortisol (SeC) and urinary cortisol. DESIGN AND PATIENTS: This was a diagnostic study. Twenty-seven patients with untreated Cushing's disease (CD untr), 21 women consuming oral contraceptive pill (OCP), 18 pregnant women, and 89 healthy subjects (controls) were enrolled. METHODS: SC and SeC at baseline and after the low-dose dexamethasone suppression test (LDDST) and urinary free cortisol (UFC) were measured. RESULTS: Midnight SC had a sensitivity of 100% in the CD untr group and a specificity of 97.7% in the controls. Specificity remained high (95.2%) in women taking OCP, while in pregnant women, it decreased to 83.3%. SC after the LDDST showed a sensitivity of 96.3% in the CD untr group; specificity was 97.7% in the controls and 90.5% in OCP women. Midnight SeC had a sensitivity of 100% in the CD untr group. SeC after the LDDST had a sensitivity of 100% in the CD untr group while specificity was 97.7% in the controls and 61.9% in women taking OCP. For UFC, sensitivity was 92.6% in the CD untr group while specificity was 97.7% in the controls and 100% in the OCP group. CONCLUSIONS: SC is a reliable parameter for the diagnosis of severe hypercortisolism, with high sensitivity and specificity. In women during pregnancy or taking OCP, the measurement of SC, identifying the free fraction, could be helpful to exclude CS.
73Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome.PubMed
Walid K Jerjes, Norman F Taylor, Timothy J Peters, et al.
Psychosom Med. 2006 Jul-Aug;68(4):578-82. doi: 10.1097/01.psy.0000222358.01096.54.
OBJECTIVES: Reduced basal hypothalamic-pituitary-adrenal (HPA) axis output in chronic fatigue syndrome (CFS) has been inferred from low cortisol levels in blood, saliva, and urine in some studies. Because > 95% of cortisol is metabolized before excretion, we assessed cortisol output by assay of both cortisol metabolites and free cortisol in 24-hour urine collections and also investigated sex differences in these between CFS and control groups. METHOD: We calculated total urinary cortisol metabolites (TCM) and cortisol metabolite ratios from individual steroid data in 40 patients (20 males and 20 females) with CFS who were free of medication or comorbid psychiatric disorder likely to influence the HPA axis. Results were compared with those of 40 healthy volunteers (20 males and 20 females) well matched for age and body mass index. Data for free cortisol was obtained on 28 of the patients and 27 of the controls. RESULTS: The mean of TCM and cortisol metabolite ratios was not significantly different between patients and controls for either sex (p > .05 for all parameters). Previously established sex differences were confirmed in our controls and were found to be similar in CFS for TCM and the ratios 11OH/11OXO, 5alpha/5beta THF, and 20OH/20OXO (see text) (p < .005, p < .05, p < .05, and p < .005, respectively). Urinary free cortisol values were numerically (but not statistically) lower in patients with CFS than controls, and correlated inversely with fatigue levels in patients. CONCLUSION: The finding of normal urinary cortisol metabolite excretion in patients with CFS is at variance with earlier reports that CFS is a hypocortisolemic state. If serum and saliva cortisol levels are lower in CFS, this would suggest that metabolic clearance of cortisol is faster in patients with CFS than controls. This study also demonstrates that sex differences must be taken into account when interpreting results in patients with CFS.
74Salivary cortisol measurement in normal-weight, obese and anorexic women: comparison with plasma cortisol.PubMed
P Putignano, A Dubini, P Toja, et al.
Eur J Endocrinol. 2001 Aug;145(2):165-71. doi: 10.1530/eje.0.1450165.
OBJECTIVE: To compare salivary, plasma and urinary free cortisol (UFC) measurements in patients with anorexia nervosa, in whom an overdrive of the hypothalamic-pituitary-adrenal (HPA) axis is well established but information on salivary cortisol is lacking, in viscerally obese patients in whom subtle abnormalities of cortisol secretion and metabolism are postulated, and in normal-weight healthy women. PARTICIPANTS AND EXPERIMENTAL DESIGN: Measurement of salivary cortisol offers a convenient way to assess the concentrations of free, biologically active cortisol in plasma in different physiopathological settings. Forty-seven drug-free, newly diagnosed women with active restrictive anorexia nervosa, 30 restrictive anorexic women undergoing chronic psychopharmacological treatment, 47 women with mild-to-moderate visceral obesity, 103 women with severe central obesity and 63 normal-weight healthy women entered the study. Salivary and blood samples were collected at 0800 h, 1700 h and 2400 h, together with three consecutive 24-h urine specimens for UFC determination. In controls and patients with anorexia nervosa (n=83), salivary and plasma cortisol were also measured after a 1-mg overnight dexamethasone suppression test (DST). In patients with anorexia nervosa, mood was rated by the Hamilton scale for anxiety and depression. RESULTS: Untreated patients with anorexia nervosa showed increased plasma and salivary cortisol and UFC concentrations (all P<0.001 compared with controls), and decreased cortisol suppression after DST in plasma and saliva (P<0.0001 and P<0.005 respectively compared with controls). These alterations were less pronounced, although still statistically significant, in treated patients with anorexia nervosa. Salivary cortisol was highly correlated with paired plasma cortisol in the whole population and after splitting the participants by group (P<0.0001). However, for plasma cortisol values greater than 500 nmol/l (the corticosteroid-binding globulin saturation point), this parallelism was lost. Taking plasma cortisol as a reference, the level of agreement for post-dexamethasone salivary and plasma cortisol was 58.9% among suppressors and 77.8% among non-suppressors (chi2 test: P<0.01). Decreased 0800 h/2400 h cortisol ratios were observed in plasma and saliva in drug-free patients with anorexia nervosa (P<0.005 and P<0.05 respectively compared with controls), and in saliva in severely obese patients (P<0.05 compared with controls). Depression and anxiety scores were unrelated to cortisol concentrations in any compartment. CONCLUSIONS: Salivary cortisol measurement is a valuable and convenient alternative to plasma cortisol measurement. It enables demonstration of the overdrive of the HPA axis in anorexia nervosa and subtle perturbations of the cortisol diurnal rhythm in women with visceral obesity. With the establishment of more specific and widely acceptable cut-off values for dynamic testing, measurement of salivary cortisol could largely replace plasma cortisol measurement.
75Cortisol trajectory, melancholia, and response to electroconvulsive therapy.PubMed
Brian J Mickey, Yarden Ginsburg, Adam F Sitzmann, et al.
J Psychiatr Res. 2018 Aug;103:46-53. doi: 10.1016/j.jpsychires.2018.05.007. Epub 2018 May 16.
While biomarkers have been used to define pathophysiological types and to optimize treatment in many areas of medicine, in psychiatry such biomarkers remain elusive. Based on previously described abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function in severe forms of depression, we hypothesized that the temporal trajectory of basal cortisol levels would vary among individuals with depression due to heterogeneity in pathophysiology, and that cortisol trajectories that reflect elevated or increasing HPA activity would predict better response to electroconvulsive therapy (ECT). To test that hypothesis, we sampled scalp hair from 39 subjects with treatment-resistant depression just before ECT. Cortisol trajectory over the 12 weeks preceding ECT was reconstructed from cortisol concentrations in sequential hair segments. Cortisol trajectories varied widely between individuals, and exploratory analyses of clinical features revealed associations with melancholia and global severity. ECT non-responders showed a decreasing trajectory (mean change -25%, 95%-CI = [-1%,-43%]) during the 8 weeks preceding ECT (group-by-time interaction, p = 0.004). The association between cortisol trajectory and subsequent ECT response was independent of clinical features. A classification algorithm showed that cortisol trajectory predicted ECT response with 80% accuracy, suggesting that this biomarker might be developed into a clinically useful test for ECT-responsive depression. In conclusion, cortisol trajectory mapped onto symptoms of melancholia and independently predicted response to ECT in this severely depressed sample. These findings deserve to be replicated in a larger sample. Cortisol trajectory holds promise as a reliable, noninvasive, inexpensive biomarker for psychiatric disorders.
76Gender Differences in Cortisol and Cortisol Receptors in Depression: A Narrative Review.PubMed
Chuin Hau Teo, Ally Chai Hui Wong, Rooba Nair Sivakumaran, et al.
Int J Mol Sci. 2023 Apr 12;24(8):7129. doi: 10.3390/ijms24087129.
Stress is known to have a significant impact on mental health. While gender differences can be found in stress response and mental disorders, there are limited studies on the neuronal mechanisms of gender differences in mental health. Here, we discuss gender and cortisol in depression as presented by recent clinical studies, as well as gender differences in the role of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in stress-associated mental disorders. When examining clinical studies drawn from PubMed/MEDLINE (National Library of Medicine) and EMBASE, salivary cortisol generally showed no gender correlation. However, young males were reported to show heightened cortisol reactivity compared to females of similar age in depression. Pubertal hormones, age, early life stressors, and types of bio-samples for cortisol measurement affected the recorded cortisol levels. The role of GRs and MRs in the HPA axis could be different between males and females during depression, with increased HPA activity and upregulated MR expression in male mice, while the inverse happened in female mice. The functional heterogeneity and imbalance of GRs and MRs in the brain may explain gender differences in mental disorders. This knowledge and understanding will support the development of gender-specific diagnostic markers involving GRs and MRs in depression.
77Sex and age differences in cortisol levels during glucagon stimulation test in children.PubMed
Camilla Borghammar, Johan Svensson, Anders Tidblad, et al.
BMC Pediatr. 2025 May 31;25(1):440. doi: 10.1186/s12887-025-05784-5.
BACKGROUND: Previous studies of glucagon stimulation test (GST) in children have shown variable results regarding the utility and reliability of the cortisol response to this test and its correlation with clinical parameters. The aim of this study was to assess cortisol levels at GST and to evaluate how clinical parameters, such as age, sex, pubertal status and Body Mass Index (BMI), correlate to cortisol levels in children. METHODS: A retrospective study of children evaluated for short stature with the GST. Cortisol, glucose and growth hormone (GH) levels at GST, as well as clinical parameters (age, sex, pubertal status, BMI), were collected from medical records. A peak cortisol of ≥ 450 nmol/L was used as a cut-off indicative of a sufficient response. Non-parametric tests were applied in the statistical analysis, and linear regression was used to examine factors affecting cortisol max at the GST. RESULTS: In total, 171 children were included; median age 7.8 years (1.0-18.0), 60 (35.1%) female, 23 (13.5%) pubertal. Of all children, 145 (84.8%) achieved a peak cortisol ≥ 450 nmol/L. There was a negative correlation between peak cortisol levels and age (Spearman's rho - 0.26, p = < 0.001). Peak cortisol levels were higher in females vs. males: 667.5 nmol/L (range 400-995) vs. 602 nmol/L (range 202-1008), p = 0.005. A higher number of boys than girls did not reach the cortisol cut-off value of 450 nmol/L (p = 0.022). The difference in maximum stimulated cortisol levels between the sexes remained after adjusting for age with a linear regression model (β (95% CI) 65.3 (15.9-114.6), p = 0.01). CONCLUSION: GST is a reliable test of the hypothalamic-pituitary-adrenal (HPA) axis in children. Girls and younger children had higher peak cortisol at GST. The results support a need for sex- and age-dependent reference values for cortisol.
78Sex hormone-dependent host-microbiome interactions and cardiovascular risk (XCVD): design of a longitudinal multi-omics cohort study.PubMed
Kristina Franz, Lajos Markó, Anja Mähler, et al.
BMJ Open. 2025 Jan 9;15(1):e087982. doi: 10.1136/bmjopen-2024-087982.
INTRODUCTION: Cardiovascular diseases (CVDs) present differently in women and men, influenced by host-microbiome interactions. The roles of sex hormones in CVD outcomes and gut microbiome in modifying these effects are poorly understood. The XCVD study examines gut microbiome mediation of sex hormone effects on CVD risk markers by observing transgender participants undergoing gender-affirming hormone therapy (GAHT), with findings expected to extrapolate to cisgender populations. METHODS AND ANALYSES: This observational, longitudinal cohort study includes baseline, 1- and 2-year follow-ups with transgender participants beginning GAHT. It involves comprehensive phenotyping and microbiome genotyping, integrating computational analyses of high-dimensional data. Microbial diversity will be assessed using gut, skin, and oral samples via 16S rRNA and shotgun metagenomic sequencing of gut samples. Blood measurements will include sex hormones, CVD risk markers, cardiometabolic parameters, cytokines, and immune cell counts. Hair samples will be analysed for cortisol. Participants will complete online questionnaires on physical activity, mental health, stress, quality of life, fatigue, sleep, pain, and gender dysphoria, tracking medication use and diet to control for confounders. Statistical analyses will integrate phenomic, lifestyle, and multi-omic data to model health effects, testing gut microbiome mediation of CVD risk as the endocrine environment shifts between that typical for cisgender men to women and vice versa. ETHICS AND DISSEMINATION: The study adheres to Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the Charité Ethical Committee (EA1/339/21). Signed informed consent will be obtained. Results will be published in peer-reviewed journals and conferences and shared as accessible summaries for participants, community groups, and the public, with participants able to view their data securely after public and patient involvement review for accessibility. TRIAL REGISTRATION NUMBER: The XCVD study was registered on ClinicalTrials.gov (NCT05334888) as 'Sex-differential host-microbiome CVD risk - a longitudinal cohort approach (XCVD)" on 4 April 2022. Data set link can be found at https://classic. CLINICALTRIALS: gov/ct2/show/NCT05334888.
79Age and sex differences in the cortisol stress reactivity and recovery among infants exposed to prenatal psychological distress.PubMed
Susanna Kortesluoma, Laura S Korhonen, Juho Pelto, et al.
Psychoneuroendocrinology. 2022 Jan;135:105580. doi: 10.1016/j.psyneuen.2021.105580. Epub 2021 Nov 6.
BACKGROUND: Altered hypothalamic-pituitary-adrenal axis (HPA) functioning is one of the potential mechanisms bridging exposure to maternal prenatal psychological distress (PPD) and later risk for offspring psychiatric illness. Research on infant cortisol stress reactivity, on scarcely studied recovery and their associations with maternal PPD is needed to clarify these mechanisms. Knowledge on sex differences in prospective settings is largely lacking. We aimed at filling these gaps by building upon our previous report showing that exposure to maternal prenatal depressive and anxiety symptoms associates with slower cortisol recovery among 10-week-old female infants. METHODS: In all, 363, 205 and 263 infants at 10 weeks, six and 14 months of age from the FinnBrain Birth Cohort Study participated in a stress test comprising of venipuncture and nasopharynx sampling. Five saliva cortisol samples were collected during each visit to measure cortisol reactivity and recovery. PPD was assessed from maternal self-reports for depressive, anxiety and pregnancy-related anxiety symptoms at gestational weeks 14, 24 and 34. RESULTS: An 11% enhanced recovery among 14-month-old females was associated with higher depressive and anxiety symptoms (95% CI=1-23%) and pregnancy-related anxiety symptoms (2-21%). No alterations in the female cortisol reactivity or male cortisol stress responses were observed. CONCLUSIONS: The opposite directions in the associations between the PPD exposure and infant cortisol recovery among 10-week-old and 14-month-old females suggest sex- and age-dependent associations between HPA axis functioning and PPD exposure among healthy infants. Follow-up is needed to characterize the impact of this altered negative feedback mechanism on later health.
80Machine learning and multi-omics in precision medicine for ME/CFS.PubMed
Katherine Huang, Brett A Lidbury, Natalie Thomas, et al.
J Transl Med. 2025 Jan 14;23(1):68. doi: 10.1186/s12967-024-05915-z.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and multifaceted disorder that defies simplistic characterisation. Traditional approaches to diagnosing and treating ME/CFS have often fallen short due to the condition's heterogeneity and the lack of validated biomarkers. The growing field of precision medicine offers a promising approach which focuses on the genetic and molecular underpinnings of individual patients. In this review, we explore how machine learning and multi-omics (genomics, transcriptomics, proteomics, and metabolomics) can transform precision medicine in ME/CFS research and healthcare. We provide an overview on machine learning concepts for analysing large-scale biological data, highlight key advancements in multi-omics biomarker discovery, data quality and integration strategies, while reflecting on ME/CFS case study examples. We also highlight several priorities, including the critical need for applying robust computational tools and collaborative data-sharing initiatives in the endeavour to unravel the biological intricacies of ME/CFS.
81Mitochondrial metabolic rescue in post-COVID-19 syndrome: MR spectroscopy insights and precision nutritional therapeutics.PubMed
Li-Zhen Chen, Qi Cai, Peng-Fei Zheng
Front Immunol. 2025 May 23;16:1597370. doi: 10.3389/fimmu.2025.1597370. eCollection 2025.
Post-COVID-19 Condition (PCC), impacting 30-90% of survivors, is characterized by persistent fatigue and metabolic dysfunction, often linked to underlying mitochondrial impairment. This review examines current evidence on mitochondrial-targeted nutrition therapies, with a focus on magnetic resonance spectroscopy (MRS) as a tool for assessing metabolic recovery. Key findings highlight reduced adenosine triphosphate (ATP) production, heightened oxidative stress, and disrupted mitochondrial biogenesis- metabolic abnormalities that closely mirror those seen in chronic fatigue syndromes. While mitochondrial dysfunction is recognized as central, debate continues on whether systemic inflammation or direct viral damage primarily drives these abnormalities. Current evidence supports nutrients, such as, CoQ10, NAC, and creatine for restoring energy metabolism and reducing oxidative stress. MRS biomarkers (τPCr, Qmax), offer valuable tools for monitoring personalized intervention. However, several limitations persist, including variability in nutritional protocols, inconsistencies in MRS methodologies, and limited consideration of microbiome-psychosocial interactions. Most clinical trials focus on short-term outcomes, lacking data on long-term efficacy or stratification based on mitochondrial dysfunction severity. Future research priorities include multi-omics investigations into mitochondrial-epigenetic interactions, the development of targeted antioxidants, and exploration of engineered microbial metabolites. Standardizing MRS protocols, validating composite endpoints, and optimizing nutrient delivery systems require interdisciplinary collaboration. This review advocates for a precision medicine approach, combining MRS-based metabolic profiling with personalized nutritional strategies, to address the multifactorial nature of PCC and advance clinical translation.