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

使用新型 11-含氧雄激素提高多囊卵巢综合征的诊断准确性和治疗效果

• 批准号: 10616771
• 负责人: ANUJA DOKRAS
• 金额: $ 8.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616771
• 关键词: Adipose tissue; Adrenal Glands; Affect; Age; Androgen Antagonists; Androgen Receptor; Androgens; Binding; Biochemical; Biological Assay; Biopsy; Body fat; Body mass index; Clinical; Clinical Trials; Confusion; Counseling; Data; Dermatologic; Detection; Development; Diagnosis; Diagnostic; Economic Burden; Endocrine System Diseases; Enzymes; Evaluation; Exhibits; Face; Funding; Gynecologic; Health; Heterogeneity; Hirsutism; Hyperandrogenism; Insulin Resistance; Intervention; Life Style Modification; Lipoproteins; Measures; Menopause; Menstruation; Metabolic; Metformin; Michigan; Oral Contraceptives; Ovarian; Patients; Phenotype; Polycystic Ovary Syndrome; Precision therapeutics; Pregnancy; Pregnancy Complications; Prevalence; Residual state; Risk; Risk Factors; Sampling; Serum; Source; Steroids; Strigiformes; Syndrome; Testing; Testosterone; Therapeutic; United States National Institutes of Health; Universities; Visual; Woman; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; cohort; comparison control; diagnostic accuracy; diagnostic criteria; experience; improved; inhibitor; insight; insulin sensitivity; laboratory experience; metabolome; novel; particle; personalized diagnostics; pill; polycystic ovarian morphology; programs; reproductive; treatment optimization

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.

项目概要 多囊卵巢综合症（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，患有多囊卵巢综合症的女性还存在以下问题： 显着的长期心脏代谢风险。高雄激素血症的证据是适当咨询和治疗的关键 管理，因为它与代谢风险增加有关。之间存在显着的异质性 患者，因为高雄激素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，新型11-氧化（oxy） 研究表明，患有多囊卵巢综合症的女性血清中雄激素及其前体含量升高 卵巢和肾上腺雄激素可能是该综合征的重要促成因素。 此外，AKR1C3 酶负责将雄激素前体转化为有效的 11keto- 患有多囊卵巢综合症的女性脂肪组织中的雄激素增加。截至目前，尚无相关信息 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。这些数据对于指导最佳治疗选择至关重要 基于雄激素代谢组。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. 确定 11-氧雄激素和 11-氧雄激素血清水平的差异 使用经验证的 12 Δ4 类固醇组，将三种 PCOS 表型中的经典雄激素与对照组进行比较。 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-氧雄激素的变化与心脏代谢危险因素的变化之间的相关性。我们 假设 FG 评分升高但经典雄激素水平正常的女性会表现出升高 与对照组相比，血清 11-氧雄激素含量增加，从而解释了观察到的临床高雄激素血症。 此外，月经不规律、多囊卵巢形态但经典雄激素正常的女性也会表现出 增加效力较弱的 11-氧雄激素。这种深入的雄激素表型如果在更大和更多样化的环境中得到验证 队列，将提高当前 PCOS 诊断标准的准确性。进一步，我们假设 二甲双胍和 LSM 将通过改善胰岛素抵抗和改变来显着降低 11-氧雄激素 脂肪组织中的 AKR1C3 活性。另一方面，OCP 可能对血清有适度的影响。 由于对肾上腺前体的抑制不充分，导致 11-氧雄激素水平升高。建议审查 一组广泛的肾上腺雄激素及其前体，并评估它们与几种的相关性 心脏代谢标志物将有助于优化不同 PCOS 表型的精准治疗。