POSTMENOPAUSAL HORMONAL REPLACEMENT THERAPY

描述(申请人提供)：高血压发病率急剧上升 绝经后，暗示雌激素对血压有有益作用 (BP)监管。然而，在认识上还存在很大差距。 绝经后高血压的发病机制及治疗。vbl.使用 神经内微电极记录正常血压节后SNA 绝经后妇女，申请人最近提供了直接证据证明 雌激素的主要交感神经抑制作用。慢性雌激素替代疗法 SNA下降30%，24小时动态血压略有下降。 这项工作最令人着迷的方面是，这些影响比 与口服雌激素相比，具有较强的透皮吸收能力。她现在想要调查： 1)通过研究绝经后她的发现的临床意义 高血压；和2)引起更大影响的潜在机制 透皮给药对SNA和BP的影响优于口服雌激素。她假设 机制涉及口服雌激素的肝脏首过代谢导致 肝脏产生的胰岛素样生长因子减少和过量 脂肪在肝脏和腹部内脏周围的沉积，是 很可能刺激SNA，并否定其主要的交感神经抑制作用 雌激素。为了检验她的机械论假说，她将需要获得新的 研究技能，包括正常血糖钳夹和核磁共振 区域脂肪分布的测量。她将使用这些技术在 探索其他临床因素，如同时服用 雄激素孕激素，很可能参与一些相同的不利因素 雌激素的代谢机制及其降压作用的否定 替补。最后，申请者将学习如何进行互补 在清醒的大鼠模型上的实验，以确定在多大程度上 交感神经系统的活动减少会导致 雌激素的降压作用。她工作的长期目标将是 该发现是最有效的雌激素制剂，可以预防或 治疗绝经后妇女高血压。

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.