Estrogen & Progesterone Effects on Orthostatic Tolerance

描述（由申请人提供）：直立不耐受是一种心血管系统功能障碍，主要影响年轻健康女性。 循环血容量减少和外周阻力降低是立位不耐受的主要机制。 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四种不同激素条件下女性的PV调节，PVR和直立耐受性：当雌激素和孕激素被抑制时;当雌激素升高时;当孕激素升高时，以及当孕激素和雌激素升高时。 具体目标是：1）确定雌激素和孕激素对细胞外液和蛋白质分布的调节，以及控制水潴留的肾脏机制。 血浆蛋白的变化改变了毛细血管的胶体渗透压梯度，并选择性地增加或减少血浆容量。 我们假设雌激素作用于血管以降低血管对蛋白质的渗透性，从而减少蛋白质和液体从血管系统中移出并增加PV。 此外，我们将测试的假设，雌激素和孕激素增加总细胞外液量（ECFV）与肾素-血管紧张素-醛固酮系统（RAAS）介导的肾脏调节。 因此，当雌激素升高时，由于更多的液体潴留和血浆中选择性的液体潴留，心血管对姿势变化的调节可能会得到改善。 我们还假设，当孕酮与雌激素同时增加时，肺静脉扩张是ECFV扩张的结果。 单独的高孕酮可以通过降低穿过毛细血管的胶体渗透压梯度和通过减弱醛固酮对肾脏的作用，减少水潴留，从而减少细胞外液和血浆体积来降低PV。 2)为了检验以下假设：雌激素相关的PVR对姿势变化的反应降低导致女性直立不耐受，孕酮拮抗这些雌激素介导的PVR变化，有助于维持直立耐受。 这些研究将确定雌激素和孕激素对直立挑战期间血容量和血管阻力之间相互作用的影响，从而可能改善女性直立不耐受的治疗。

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.