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.

项目摘要 多囊卵巢综合征（PCOS）是复制年龄女性中最常见的内分泌疾病。在 除了妇科和生殖问题外，有PCOS的妇女有众所周知 重大的长期心脏代谢风险。超雄激素主义的证据是适当咨询和 管理层由于其与代谢风险增加的关联。之间存在明显的异质性 患者，由于超雄激素是通过卵巢源经典雄激素水平升高的诊断，即 总和睾丸激素和/或高铁曼 - 加尔维（FG）毛毛学得分。这导致病人 对诊断经验和咨询的不满。最近，新型11氧化（氧） 雄激素及其前体已被证明是PCOS女性的血清中升高的 卵巢和肾上腺雄激素的可能性可能是该综合征的重要因素。 此外，负责将雄激素前体转化为潜在的11酮的酶AKR1C3 雄激素在PCOS女性的脂肪组织中增加。到目前为止，还没有有关 一线治疗（例如口服避孕药（OCP），二甲双胍和生活方式修改）的影响 （LSM）在血清11-氧和树脂水平上。这些数据对于指导疗法的最佳选择至关重要 基于雄激素代谢组。我们建议使用三个NIH的残留去识别的血清样品 为两个目标提供了资助的临床试验。 AIM 1。确定11-氧和细菌的血清水平差异和 与使用12 ∆4类固醇的对照组相比，三种PCOS表型中的经典雄激素与对照组相比。 AIM 2。确定在干预OCP，二甲双胍或LSM之后的11-氧和生物体的变化以及 确定11-氧和糖的变化与心脏代谢风险因素的变化之间的相关性。 假设FG得分升高但经典雄激素水平的女性会增加 与对照相比，在血清11-氧和基因的血清中，从而解释了观察到的临床超雄激素。 此外，具有不规则月经的女性，多囊卵巢形态但正常的经典雄激素将存在 增加潜在的11-氧和果实的增加。这种深层的雄激素表型，如果在较大和潜水员中得到验证 队列将提高PCOS当前诊断标准的精度。此外，我们假设 二甲双胍和LSM将通过改善胰岛素耐药性和改变而显着降低11-氧和果糖 脂肪组织中的AKR1C3活性。另一方面，OCP可能会对串行产生适中的影响 由于肾上腺前体抑制不足而导致的11-氧和树脂水平。提议的检查 广泛的肾上腺雄激素及其前体以及与几个相关性的评估 心脏代谢标记将允许在不同的PCOS表型中优化精确治疗。