Estrogen & Progesterone Effects on Orthostatic Tolerance

描述(由申请人提供)：矫形不耐受是一种心血管系统功能障碍，主要影响年轻、健康的女性。循环血容量减少和外周阻力低是立位耐受的主要机制。雌激素和孕激素调节血浆容量(PV)和外周血管阻力(PVR)。本研究的目的是比较女性在四种不同激素状态下的PV调节、PVR和立位耐受性：当雌激素和孕酮被抑制时；当雌激素升高；当孕酮升高时；当孕酮和雌激素升高时。其具体目的是：1)确定雌激素和孕激素对细胞外液和蛋白质分布的调节，以及肾脏控制水分滞留的机制。血浆蛋白的变化改变了毛细血管间的胶体渗透压梯度，选择性地增加或减少了血浆容量。我们假设雌激素作用于血管，降低血管对蛋白质的通透性，从而减少蛋白质和液体从血管系统中流出，增加PV。此外，我们将验证雌激素和孕激素增加细胞外液体总量(ECFV)的假说，该假说与肾素-血管紧张素-醛固酮系统(RAAS)介导的肾脏调节有关。因此，当雌激素升高时，心血管对体位变化的适应可能会得到改善，这是由于更多的液体滞留和选择性的液体滞留在血浆中。我们还假设，当孕激素随着雌激素的增加而增加时，PV扩张是ECFV扩张的结果。高孕酮本身可能通过降低毛细血管间胶体渗透压梯度和减弱对肾脏的醛固酮作用，减少水分滞留，从而减少细胞外液和血浆容量，从而减少PV。2)验证这一假说，即雌激素相关的PVR对体位变化的反应减少有助于女性立位耐受，而孕激素拮抗这些雌激素介导的PVR变化，帮助维持立位耐受。这些研究将确定雌激素和孕激素在立位挑战中对血容量和血管阻力之间相互作用的影响，从而可能改善女性立位耐受性的治疗。

DESCRIPTION (provided by applicant): Orthostastic intolerance is a dysfunction of the cardiovascular system that affects primarily young, healthy women. Diminished circulating blood volume and low peripheral resistance are primary mechanisms for orthostatic intolerance. Estrogen and progesterone modulate both plasma volume (PV) and peripheral vascular resistance (PVR). The purpose of this study is to compare PV regulation, PVR and orthostatic tolerance in women under four different hormonal conditions: when estrogen and progesterone are suppressed; when estrogen is elevated; when progesterone is elevated, and when progesterone and estrogen are elevated. The Specific Aims are: 1) To determine estrogen and progesterone modulation of extracellular fluid and protein distribution, and renal mechanisms controlling water retention. Plasma protein changes alter the colloid osmotic pressure gradient across capillaries and selectively enhance or reduce plasma volume. We hypothesize that estrogen acts on vessels to reduce vascular permeability to proteins, thereby reducing protein and fluid movement out of the vasculature and increasing PV. Moreover, we will test the hypothesis that estrogen and progesterone increase total extracellular fluid volume (ECFV) associated with renin-angiotensin-aldosterone system (RAAS)-mediated renal adjustments. Thus cardiovascular adjustments to postural changes may be improved when estrogen is elevated due to greater fluid retention and due to selective fluid retention in the plasma. We also hypothesize that PV expansion is the consequence of ECFV expansion when progesterone is increased concomitant with estrogen. High progesterone alone may reduce PV both by reducing colloid osmotic pressure gradient across capillaries and by attenuating aldosterone actions on the kidney, reducing water retention, and thus extracellular fluid and plasma volumes. 2) To test the hypothesis that estrogen-related reductions in PVR response to posture changes contribute to orthostatic intolerance in women, and progesterone antagonizes these estrogen mediated changes in PVR, helping to maintain orthostatic tolerance. These studies will define the impact of estrogen and progesterone on the interaction between blood volume and vascular resistance during orthostatic challenges, and thus may improve treatment of orthostatic intolerance in women.