Ensemble Control of ACTH Secretion: Impact of Gender

描述（由申请人提供）：糖皮质激素的生理量对于维持葡萄糖稳态、血压、免疫功能、神经元兴奋性、健康和长寿是至关重要的。在实验动物中，性腺激素和性别控制调节促肾上腺皮质激素（ACTH）和糖皮质激素分泌的关键机制。关于性类固醇如何调节人类促皮质轴的研究是不完整的、相互矛盾的、受年龄影响的困扰以及受实验设计和分析的限制。为了解决这些基本的知识缺陷，需要4种研究策略，即：(1)在gnrh受体拮抗剂抑制性腺期间，雌激素或雄激素受体（ER和AR）同时阻断或不同时阻断雌激素或雄激素受体（ER和AR）时，补充雌二醇或睾酮；(2)在肾上腺甾体源性阻断期间，延迟（积分）和快速（速率敏感）皮质醇负反馈的分级施加；(3)人CRH和AVP联合剂量依赖性刺激ACTH分泌；(4) ACTH分泌改变的三方（CRH、AVP和皮质醇）调节的分析重建。因此，我们的目标是根据3个基本假设来分析健康老年人应激适应性控制中强烈的性别相关差异的机制基础：假设1 .雌二醇会放大CRH和AVP的剂量依赖性作用，增强CRH/AVP的协同作用，并在恒定的矿物质皮质激素可用性下通过3层皮质醇抑制来消除延迟（积分）负反馈。雌激素的作用会被选择性内质网拮抗剂阻断。假设2。睾酮会增强CRH和AVP的剂量依赖性刺激，增加2肽协同作用，减弱皮质醇逐渐升高的延迟负反馈。睾酮的作用将被芳香化酶抑制剂所抑制，并被特异性AR拮抗剂所增强。假设3。雌二醇和睾酮将缓解快速的（速率敏感的）负反馈，通过剂量变化的皮质醇脉冲，以一种被内质网拮抗剂和芳香化酶抑制剂逆转的方式。这些实验的结果应该为在人类糖皮质激素调节中转导性别差异的基本机制提供独特的见解。因此，期望是促进新的诊断和干预策略，以避免妇女和男子的受损或过度的压力适应的后遗症。公众的总结。这些研究将阐明女性和男性类固醇如何控制人类应激激素分泌中的性别特异性适应。其目标是揭示检测、预防和治疗衰老、疾病和疾病中异常应激适应反应的新方法。

DESCRIPTION (provided by applicant): Physiological amounts of glucocorticoid are crucial to maintain glucose homeostasis, blood pressure, immune function, neuronal excitability, well being and longevity in the face of diverse stressors. Gonadal sex steroids and gender govern key mechanisms that mediate the adaptive control of adrenocorticotropin (ACTH) and glucocorticoid secretion in laboratory animals. Studies of how sex steroids regulate the human corticotropic axis are fragmentary, contradictory, confounded by age effects and limited by experimental design and analyses. To address these fundamental knowledge deficits requires 4 investigative strategies, viz.: (1) addback of estradiol or testosterone during gonadal suppression by a GnRH-receptor antagonist with and without concomitant blockade of the estrogen or androgen receptor (ER and AR); (2) graded " imposition of delayed (integral) and rapid (rate-sensitive) cortisol negative feedback during adrenal steroidogenic blockade; (3) joint dose-dependent stimulation of ACTH secretion by human CRH and AVP; and (4) analytical reconstruction of altered tripartite (CRH, AVP and cortisol) regulation of ACTH secretion. The goal thereby is to parse the mechanistic bases of strong gender-associated distinctions in stress- adaptive control in healthy older adults according to 3 fundamental hypotheses: Hypothesis I. Estradiol will amplify dose-dependent actions of CRH and AVP, augment CRH/AVP synergy and mute delayed (integral) negative feedback by 3 strata of cortisol inhibition under constant mineralocorticoid availability. Estrogen's effects will be blocked by a selective ER antagonist. Hypothesis II. Testosterone will potentiate dose-dependent stimulation by CRH and AVP, increase 2- peptide synergy and attenuate delayed negative feedback by graded cortisol elevations. Testosterone's actions will be opposed by an aromatase inhibitor, and augmented by a specific AR antagonist. Hypothesis III. Estradiol and testosterone will relieve rapid (rate-sensitive) negative feedback by dose- varying pulses of cortisol in a manner reversed by an ER antagonist and aromatase inhibitor. The outcomes of these experiments should provide unique insights into the basic mechanisms that transduce gender distinctions in glucocorticoid regulation in the human. The expectation thereby is to foster novel diagnostic and interventional strategies to avert the sequelae of impaired or excessive stress adaptations in women and men. Public Summary. These studies will elucidate how female and male sex steroids govern gender-specific adaptations in stress-hormone secretion in humans. The goal is to unveil new ways to detect, prevent and treat abnormal stress-adaptive responses in aging, illness and disease.