Ensemble Control of ACTH Secretion: Impact of Gender

描述(申请人提供)：生理量的糖皮质激素对于在不同的压力下保持葡萄糖稳态、血压、免疫功能、神经兴奋性、幸福感和长寿至关重要。性腺激素和性别控制着实验动物的促肾上腺皮质激素(ACTH)和糖皮质激素分泌的适应性调节的关键机制。性类固醇如何调节人类皮质轴的研究是零散的、相互矛盾的，受到年龄效应的混淆，并受到实验设计和分析的限制。要解决这些基础知识缺陷，需要4种研究策略，即：(1)性腺抑制时GnRH受体拮抗剂使雌二醇或睾酮回升，同时或不同时阻断雌激素或雄激素受体(ER和AR)；(2)在肾上腺类固醇激素生成阻断期间，分级“施加延迟(积分)和快速(率敏感)的皮质醇负反馈；(3)人CRH和AVP联合剂量依赖地刺激ACTH分泌；以及(4)分析重建改变的三方(CRH、AVP和皮质醇)对ACTH分泌的调节。因此，我们的目标是根据3个基本假设来分析健康老年人在应激适应控制中的强烈性别差异的机制基础：假设1.在恒定的盐皮质激素供应下，雌二醇将放大CRH和AVP的剂量依赖作用，增强CRH/AVP的协同作用，并通过3层皮质醇抑制抑制延迟(积分)负反馈。雌激素的作用将被选择性雌激素受体拮抗剂阻断。假设II：睾酮将增强CRH和AVP的剂量依赖性刺激，增强2-肽的协同作用，并通过皮质醇的分级升高来减弱延迟的负反馈。睾丸激素的作用将被芳香酶抑制剂所对抗，并被一种特定的AR拮抗剂所增强。假设III：雌激素和睾酮可以通过剂量变化的皮质醇脉冲缓解快速的(对速率敏感的)负反馈，这种作用被雌激素受体拮抗剂和芳香酶抑制剂逆转。这些实验的结果应该为人类糖皮质激素调节的性别差异的基本机制提供独特的见解。因此，人们的期望是培育新的诊断和干预策略，以避免女性和男性因压力适应受损或过度适应而产生的后遗症。公共摘要。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。其目标是揭示新的方法来检测、预防和治疗衰老、疾病和疾病中的异常压力适应反应。

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.