Use of novel 11-oxygenated androgens to improve diagnostic accuracy and therapeutics in polycystic ovary syndrome

项目摘要 多囊卵巢综合征(PCOS)是育龄妇女最常见的内分泌疾病。在……里面 除了妇科和生殖问题外，众所周知，患有多囊卵巢综合征的妇女有 严重的长期心脏代谢风险。高雄激素血症的证据是适当咨询和 管理，因为它与增加的代谢风险有关。它们之间存在着显著的异质性 患者，由于高雄激素血症是通过卵巢来源的经典雄激素水平升高来诊断的，即， 总的和游离的睾酮和/或高的费里曼-加尔韦(FG)多毛评分。这导致了耐心 对诊断经验和咨询都不满意。最近，新的11-含氧(氧) 多囊卵巢综合征患者的血清中雄激素及其前体水平升高。 卵巢和肾上腺雄激素可能都是导致这种综合征的重要因素。 此外，AKR1C3酶负责将雄激素前体转化为有效的11keto-1。 多囊卵巢综合征患者脂肪组织中雄激素的含量增加。到目前为止，没有关于 口服避孕药(OCPs)、二甲双胍和改变生活方式等一线治疗的影响 (LSM)对血清11-氧雄激素水平的影响。这些数据将是指导最佳治疗选择的关键 基于雄激素代谢组。我们建议使用来自三个NIH的残留的未鉴定的血清样本 资助两个目标的临床试验。目的1.确定血清11-氧雄激素水平的差异 将三种多囊卵巢综合征表型中的经典雄激素与使用12种∆4类固醇的验证小组的对照组进行比较。 目的2.测定口服避孕药、二甲双胍或LSM干预后11-氧雄激素水平的变化。 确定11-氧雄激素变化与心脏代谢危险因素变化之间的相关性。我们 假设FG评分升高但经典雄激素水平正常的女性将表现出增加 与对照组比较，从而解释观察到的临床高雄激素血症。 此外，月经不规律、多囊卵巢形态但典型雄激素正常的女性将表现出 效力较低的11-氧雄激素的增加。这种深度雄激素表型，如果在更大和多样化的情况下得到验证 这将提高目前多囊卵巢综合征诊断标准的精确度。此外，我们假设 二甲双胍和LSM通过改善胰岛素抵抗和改变 脂肪组织中AKR1C3的活性。另一方面，有机氯农药可能会对血清产生轻微的影响。 肾上腺前体抑制不足导致的11-氧雄激素水平。建议进行的研究 肾上腺雄激素及其前体的广泛小组及其与几种激素的相关性评估 心脏代谢标志物将允许对不同表型的PCOS进行精确治疗。

Project Summary Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in reproductive age women. In addition to gynecologic and reproductive problems, it is well established that women with PCOS have significant long term cardiometabolic risk. Evidence of hyperandrogenism is key to appropriate counselling and management due to its association with increased metabolic risk. There is significant heterogeneity amongst patients, as hyperandrogenism is diagnosed by elevated levels of classic androgens of ovarian source namely, total and free testosterone and/or high Ferriman-Gallwey (FG) hirsutism score. This leads to patient dissatisfaction with both the diagnostic experience and counselling. Recently, novel 11-oxygenated (oxy) androgens and their precursors have been shown to be elevated in sera from women with PCOS raising the possibility that both ovarian and adrenal androgens might be significant contributors to this syndrome. Moreover, the enzyme AKR1C3 responsible for the conversion of androgen precursors to potent 11keto- androgens, is increased in the adipose tissues of women with PCOS. As yet, there is no information on the impact of first-line treatments such as oral contraceptive pills (OCPs), metformin and lifestyle modifications (LSM) on serum 11-oxyandrogens levels. This data will be essential to guide the optimal choice of therapies based on the androgen metabolome. We propose to use residual de-identified serum samples from three NIH funded clinical trials for two aims. Aim 1. Determine differences in serum levels of 11-oxyandrogens and classic androgens in three PCOS phenotypes compared to controls using a validated panel of 12 ∆4 steroids. Aim 2. To determine the change in 11-oxyandrogens after interventions with OCPs, metformin or LSM and determine the correlation between change in 11-oxyandrogens and change in cardiometabolic risk factors. We hypothesize that women with elevated FG scores but normal classic androgens levels will exhibit an increase in serum 11-oxyandrogens compared to controls, thereby explaining the observed clinical hyperandrogenism. Also, women with irregular menses, polycystic ovary morphology but normal classic androgens will exhibit an increase in less potent 11-oxyandrogens. This deep androgen phenotyping, if validated in larger and diverse cohorts, will improve the precision of current diagnostic criteria for PCOS. Further, we hypothesize that metformin and LSM will significantly decrease 11-oxyandrogens by improving insulin resistance and altering AKR1C3 activity in the adipose tissue. On the other hand, OCPs will likely have a modest effect on serum levels of 11-oxyandrogens due to inadequate suppression of adrenal precursors. The proposed examination of a broad panel of adrenal androgens and their precursors and assessment of their correlations with several cardiometabolic markers will allow optimization of precision therapy in different PCOS phenotypes.