Ensemble Control of ACTH Secretion: Impact of Gender

ACTH 分泌的整体控制：性别的影响

• 批准号: 7408562
• 负责人: JOHANNES D VELDHUIS
• 金额: $ 29.01万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408562
• 关键词: Abarelix; Address; Adrenal Cortex Hormones; Adrenal Glands; Age; Aging; Agonist; Androgen Receptor; Androgens; Animals; Arginine; Aromatase Inhibitors; Attenuated; Back; Bicalutamide; Blood; Blood Pressure; CRH gene; Clinical Trials; Competence; Confounding Factors (Epidemiology); Corticotropin; Corticotropin Receptors; Corticotropin-Releasing Hormone; Disease; Dose; Elderly; Elevation; Enzymes; Estradiol; Estrogens; Experimental Designs; Face; Failure; Feedback; Female; Fostering; Fulvestrant; Gender; Glucocorticoids; Goals; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone Receptor; HPSE gene; Hormones; Hospitalization; Human; Hydrocortisone; Hypothalamic structure; Immune; Infusion procedures; Intervention; Investigation; Joints; Knowledge; Laboratory Animals; Longevity; Mediating; Mineralocorticoids; Muscle; Neurons; Neurosecretory Systems; Outcome; Output; Pathway interactions; Peptides; Personal Satisfaction; Physiologic pulse; Physiological; Pituitary Gland; Placebos; Postmenopause; Prevention; Pulse taking; Rate; Regulation; Saline; Sex Characteristics; Signal Transduction; Sodium; Steroids; Stress; Structure; Testing; Testosterone; Vasopressins; Woman; Work; age effect; analytical tool; anastrozole; base; blood glucose regulation; bone; concept; disability; expectation; feeding; hypothalamic-pituitary-adrenal axis; immune function; inhibitor/antagonist; innovation; insight; male; men; neuronal excitability; novel; novel diagnostics; prevent; reconstruction; research study; response; salt balance; sex; stressor

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.

描述（由申请人提供）：生理量的糖皮质激素对于在面对不同压力源时维持葡萄糖稳态、血压、免疫功能、神经元兴奋性、健康和长寿至关重要。性腺性类固醇和性别控制介导实验动物促肾上腺皮质激素（ACTH）和糖皮质激素分泌的适应性控制的关键机制。关于性类固醇如何调节人类促肾上腺皮质轴的研究是零碎的、相互矛盾的、受年龄影响的混淆以及实验设计和分析的限制。为了解决这些基本知识缺陷，需要 4 个研究策略，即：（1）在 GnRH 受体拮抗剂性腺抑制过程中添加雌二醇或睾酮，并同时阻断或不阻断雌激素或雄激素受体（ER 和 AR）； (2) 在肾上腺类固醇激素阻断过程中分级施加延迟（整体）和快速（速率敏感）皮质醇负反馈；(3) 人 CRH 和 AVP 对 ACTH 分泌的联合剂量依赖性刺激；(4) 分析重建改变 ACTH 分泌的三方（CRH、AVP 和皮质醇）调节 目标是根据 3 解析健康老年人压力适应性控制中强烈的性别相关差异的机制基础。基本假设：假设 I。雌二醇将放大 CRH 和 AVP 的剂量依赖性作用，增强 CRH/AVP 协同作用，并通过 3 层皮质醇抑制来抑制延迟（整体）负反馈，在恒定的盐皮质激素可用性下，雌激素的作用将被选择性阻断。 ER 拮抗剂。睾酮会增强 CRH 和 AVP 的剂量依赖性刺激，增加 2-肽协同作用并减弱延迟阴性。皮质醇分级升高的反馈会受到芳香酶抑制剂的抑制，并受到特定 AR 拮抗剂的增强。假设三。雌二醇和睾酮将通过剂量变化的皮质醇脉冲以 ER 拮抗剂和芳香酶抑制剂逆转的方式缓解快速（速率敏感）负反馈。这些实验的结果应该为改变人类糖皮质激素调节性别差异的基本机制提供独特的见解。因此，期望培育新的诊断和干预策略，以避免女性和男性因应激适应受损或过度而产生后遗症。公开摘要。这些研究将阐明女性和男性性类固醇如何控制人类应激激素分泌的性别特异性适应。其目标是揭示检测、预防和治疗衰老、疾病等异常压力适应性反应的新方法。