POSTMENOPAUSAL HORMONAL REPLACEMENT THERAPY

描述（申请人提供）：高血压发病率急剧上升 绝经后，暗示雌激素对血压的有益作用 (BP)调控 然而，在理解方面仍存在很大差距， 绝经后高血压的潜在机制和治疗。 使用 神经内微电极记录正常血压者节后SNA 绝经后妇女，申请人最近提供了直接证据， 雌激素的主要交感神经抑制作用。 慢性雌激素替代 SNA下降30%，并导致24小时动态血压小幅下降。 这项工作最吸引人的地方在于， 比口服雌激素更有效。 她现在想调查： 1)她通过研究绝经后妇女， 高血压;和2）导致更大影响的潜在机制 经皮给药比口服雌激素对SNA和BP的影响更大。 她推测， 机制涉及口服雌激素的首过肝脏代谢， 肝脏胰岛素样生长因子的产生减少， 脂肪沉积在肝脏和腹部内脏周围， 可能会刺激SNA，并否定初级交感神经抑制作用， 雌激素. 为了验证她的机械假说，她需要获得新的 研究技能，包括正常血糖钳夹和核磁共振 测量区域脂肪分布。 她将使用这些技术， 探索其他临床因素，如伴随给药 雄激素孕激素，这可能是从事一些相同的不利 代谢机制和否定雌激素的降压作用 更换. 最后，申请人将学习执行补充 在清醒的大鼠模型中进行实验，以确定 交感神经系统的活动减少导致 雌激素的降压作用。 她工作的长期目标是 发现最有效的雌激素制剂，可以防止或 治疗绝经后妇女的高血压。

DESCRIPTION (provided by applicant): Hypertension incidence rises sharply after menopause, implicating a beneficial effect of estrogen on blood pressure (BP) regulation. However, there still are large gaps in the understanding of the underlying mechanisms and treatment of postmenopausal hypertension. Using intraneural microelectrodes to record postganglionic SNA in normotensive postmenopausal women, the applicant recently provided direct evidence for a major sympathoinhibitory effect of estrogen. Chronic estrogen replacement decreased SNA by 30% and caused a small decrease in 24-hour ambulatory BP. The most fascinating aspect of the work is that these effects were much more robust with transdermal than oral estrogen. She now wants to investigate: 1) the clinical importance of her findings by studying postmenopausal hypertension; and 2) underlying mechanism causing a greater effect of transdermal than oral estrogen on SNA and BP. She hypothesizes that the mechanism involves first-pass hepatic metabolism of oral estrogen leading to decreased hepatic production of insulin-like growth factor and excessive deposition of fat in the liver and around the abdominal viscera, factors which are likely to stimulate SNA and negate a primary sympathoinhibitory action of estrogen. To test her mechanistic hypothesis, she will need to acquire new research skills including euglycemic clamps and nuclear magnetic resonance measurements of regional fat distribution. She will use these techniques in exploring other clinical factors, such as concomitant administration of androgenic progestins, that are likely to engage some of the same adverse metabolic mechanisms and negate the antihypertensive effect of estrogen replacement. Finally, the applicant will learn to perform complementary experiments in a conscious rat model to determine the extent to which decreased activity of the sympathetic nervous system causes the antihypertensive effect of estrogen. The long-term goal of her work would be the discovery the most effective estrogen preparation that can prevent or treat hypertension in women after menopause.