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 除了妇科和生殖问题外，众所周知，患有PCOS的女性 显著长期心脏代谢风险。高雄激素血症的证据是适当咨询的关键， 管理，因为它与代谢风险增加有关。存在显著的异质性， 患者，因为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， 总睾酮和游离睾酮和/或高Ferriman-Gallwey（FG）多毛症评分。这导致患者 对诊断经验和咨询都不满意。最近，新的11-氧合（氧） 雄激素及其前体已被证明在PCOS妇女的血清中升高， 卵巢和肾上腺雄激素可能是这种综合征的重要贡献者。 此外，AKR 1C 3酶负责雄激素前体转化为有效的11-酮- 雄激素在PCOS女性的脂肪组织中增加。到目前为止，还没有关于 口服避孕药（OCP）、二甲双胍和生活方式改变等一线治疗的影响 (LSM)对血清11-氧雄激素水平的影响这些数据对于指导治疗的最佳选择至关重要 基于雄激素代谢组学我们建议使用来自三个NIH的残留去识别血清样本 资助临床试验有两个目的目标1.测定血清11-氧雄激素水平的差异， 经典的雄激素在三个PCOS表型相比，对照组使用验证面板的12 × 14类固醇。 目标2.确定OCP、二甲双胍或LSM干预后11-氧雄激素的变化， 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分数升高但经典雄激素水平正常的女性将表现出增加 血清11-氧雄激素与对照组相比，从而解释了观察到的临床高雄激素血症。 此外，月经不规则，多囊卵巢形态但正常的经典雄激素的妇女将表现出 11-氧雄激素作用较弱。这种深层雄激素表型，如果在更大的和多样化的 队列，将提高目前PCOS诊断标准的准确性。此外，我们假设， 二甲双胍和LSM将通过改善胰岛素抵抗和改变胰岛素抵抗来显著降低11-氧雄激素。 脂肪组织中的AKR 1C 3活性。另一方面，OCP可能对血清中的 11-氧雄激素水平由于肾上腺前体抑制不足。拟议的审查 一个广泛的面板肾上腺雄激素及其前体和评估其相关性与几个 心脏代谢标志物将允许在不同PCOS表型中优化精确治疗。

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.