Department of Psychiatry, University of California, San Diego, Health Sciences, La Jolla, CA, United States.
Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
Psychoneuroendocrinology. 2018 Aug;94:72-82. doi: 10.1016/j.psyneuen.2018.05.007. Epub 2018 May 4.
Women and men differ in their risk for developing stress-related conditions such as alcohol use and anxiety disorders and there are gender differences in the typical sequence in which these disorders co-occur. However, the neural systems underlying these gender-biased psychopathologies and clinical course modifiers in humans are poorly understood and may involve both central and peripheral mechanisms regulating the limbic-hypothalamic-pituitary-adrenal axis. In the present randomized, double blind, placebo-controlled, triple-dummy crossover study, we juxtaposed a centrally-acting, citalopram (2 mg/unit BMI) neuroendocrine stimulation test with a peripherally-acting, dexamethasone (Dex) (1.5 mg)/corticotropin-releasing factor (CRF) (1 μg/kg) test in euthymic women (N = 38) and men (N = 44) with (54%) and without histories of alcohol dependence to determine whether sex, alcohol dependence or both influenced the adrenocorticotropic hormone (ACTH) and cortisol responses to the pharmacological challenges and to identify the loci of these effects. We found that central serotonergic mechanisms, along with differences in pituitary and adrenal sensitivity, mediated sexually-diergic ACTH and cortisol responses in a stressor-specific manner regardless of a personal history of alcohol dependence. Specifically, women exhibited a greater response to the Dex/CRF test than they did the citalopram test while men exhibited the opposite pattern of results. Women also had more robust ACTH, cortisol and body temperature responses to Dex/CRF than men, and exhibited a shift in their adrenal glands' sensitivity to ACTH as measured by the cortisol/log (ACTH) ratio during that session in contrast to the other test days. Our findings indicate that central serotonergic and peripheral mechanisms both play roles in mediating sexually dimorphic, stressor-specific endocrine responses in humans regardless of alcohol dependence history.
女性和男性在应激相关疾病的发病风险上存在差异，如酒精使用和焦虑障碍，而且这些疾病的典型发生顺序也存在性别差异。然而，人类中这些性别偏见的精神病理学和临床病程修饰因子的神经机制还知之甚少，可能涉及调节边缘-下丘脑-垂体-肾上腺轴的中枢和外周机制。在本项随机、双盲、安慰剂对照、三盲交叉研究中，我们将一种中枢作用的西酞普兰（2mg/单位 BMI）神经内分泌刺激试验与一种外周作用的地塞米松（Dex）（1.5mg）/促皮质素释放因子（CRF）（1μg/kg）试验并列在心境正常的女性（N=38）和男性（N=44）中进行，这些被试（54%）和不（46%）有酒精依赖史，以确定性别、酒精依赖或两者是否影响了药物挑战的促肾上腺皮质激素（ACTH）和皮质醇反应，并确定这些效应的部位。我们发现，中枢 5-羟色胺能机制以及垂体和肾上腺敏感性的差异以一种应激特异性的方式介导了性别差异的 ACTH 和皮质醇反应，而不论是否有酒精依赖的个人史。具体而言，与西酞普兰试验相比，女性对 Dex/CRF 试验的反应更大，而男性则表现出相反的结果模式。女性对 Dex/CRF 的 ACTH、皮质醇和体温反应也比男性更强，而且与其他测试日相比，在该测试期间，她们的肾上腺对 ACTH 的敏感性的变化表现为皮质醇/对数（ACTH）比值的变化。我们的研究结果表明，中枢 5-羟色胺能和外周机制都在介导人类中应激特异性的性别差异内分泌反应中发挥作用，而不论是否有酒精依赖史。
