MENTORED PATIENT ORIENTED RESEARCH CAREER DEVELOPMENT AW

提案（改编自申请人摘要）：绝经后雌激素 替代疗法（ERT）已经成为老年妇女中可接受的干预。 最近发表的心脏和雌激素和孕激素替代品 研究（HERS）做出了启动绝经后ERT的艰难决定 对临床医生来说更加困难。 小密度低密度脂蛋白 (LDL)和纤溶酶原激活物抑制剂1型（派-1）是 冠状动脉疾病（CAD）随着绝经而增加，可能代表 未来个体CAD风险的标志物。 建议的主要目标 这项研究是为了调查那些在整个研究期间发展出小而密集的LDL的女性， 绝经期将选择性地受益于透皮ERT。 的机制 还将通过测量肝脏中LDL大小的变化来研究LDL大小变化的潜在原因。 脂肪酶活性，胆固醇酯转移蛋白（CETP）活性， 甘油三酯（TG）水平、体脂分布和肝脂酶基因 启动子多态性，所有已知的影响LDL大小。 调查人员将 还可以确定绝经后出现小而密LDL的妇女是否也 派-1升高。 这是一项前瞻性、随机、非盲交叉研究 两组绝经后妇女口服和透皮ERT的比较试验 从绝经前开始就被跟踪的女性 二十三 绝经后妇女在绝经期出现小而密的LDL， 与23名绝经后妇女相比，这些妇女仍然具有大的，漂浮的LDL。 他们将被随机分配接受为期6个月的经皮或口服ERT治疗 随后在第二次ERT开始前进行6个月的洗脱期 当然了 这项研究将确定是否有一个首选的方法， 绝经后ERT在发生小而密LDL的女性亚组中， 绝经 他们还将阐明这些转变背后的机制 在LDL大小与口服和透皮ERT。

PROPOSAL (Adapted from the applicant's abstract): Postmenopausal estrogen replacement therapy (ERT) has become an accepted intervention in aging women. The recent publication of the Heart and Estrogen and Progestin Replacement Study (HERS) has made the difficult decision to initiate postmenopausal ERT even more difficult for clinicians. Both small, dense low density lipoprotein (LDL) and plasminogen activator inhibitor Type 1 (PAI-1) are risk factors for coronary artery disease (CAD) that increase with menopause and may represent markers of future individual CAD risk. The primary objective of the proposed study is to investigate whether women who develop small, dense LDL across the menopause will selectively benefit from transdermal ERT. The mechanisms underlying the changes in LDL size will also be studied by measuring hepatic lipase activity, cholesteryl ester transfer protein (CETP) activity, triglyceride (TG) levels, body fat distribution and the hepatic lipase gene promoter polymorphism, all known to affect LDL size. The investigators will also determine whether women who develop small, dense LDL with menopause also have elevated PAI-1. This is a prospective, randomized non-blinded crossover trial comparing oral and transdermal ERT in two groups of postmenopausal women who have been followed since the premenopausal state. Twenty-three postmenopausal women who have developed small, dense LDL with menopause will be compared to 23 postmenopausal women who remain with large, buoyant LDL. They will be randomized to a six-month course of transdermal or oral ERT followed by a six-month washout period before the start of the second ERT course. This study will determine if there is a preferred method of postmenopausal ERT in the subset of women who develop small, dense LDL after menopause. They will also elucidate the mechanisms that underlie the shifts in LDL size with oral and transdermal ERT.