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Adrenal Zonation and Androgen Synthesis

肾上腺分区和雄激素合成

基本信息

批准号：
8927991
负责人：
Adina F Turcu
金额：
$ 3.73万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-06 至 2016-03-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927991
关键词：
11-ketotestosterone Adrenal Cortex Adrenal Gland Tissue Adrenal Glands Adult Anabolism Androgens Androstenedione Biological Markers Blood specimen Bypass C19 steroid CYP11B1 gene CYP17A1 gene CYP21A2 gene Carbon Characteristics Child Chronic Clinical Coenzymes Congenital adrenal hyperplasia Corticotropin Cushing Syndrome Cytochromes b5 Data Enzymes Genetic Glucocorticoids Goals Gonadal structure Hereditary Disease Human Hydrocortisone Hydroxyprogesterone Hydroxysteroid Dehydrogenases Inorganic Sulfates Liquid Chromatography Measurement Measures Mixed Function Oxygenases Monitor Mutation Oxidoreductase Pathway interactions Patients Production Proteins Research Route Serum Site Stanolone Steroid 17-alpha-monooxygenase Steroid 21-Monooxygenase Steroids Testosterone Tissues Unspecified or Sulfate Ion Sulfates Virilism Zona Fasciculata Zona Glomerulosa Zona Reticularis cofactor dehydroepiandrosterone fetal girls improved novel public health relevance tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): The most common form of congenital adrenal hyperplasia, 21-hydroxylase deficiency (21OHD), is also one of the most common genetic diseases. A hallmark characteristic of all patients with 21OHD is adrenal androgen excess. These androgens derive from accumulation of precursors, such as 17-hydroxyprogesterone (17OHP4), proximal to the defective enzymatic step, which are converted to testosterone (T) via accessible pathways involving steroid 17-hydroxylase/17, 20-lyase (CYP17A1) under the stimulation of cofactor protein cytochrome b5 (CYB5A). Dehydroepiandrosterone (DHEA), its sulfate (DHEAS) and androstenedione (AD) are thought to be the major androgen precursors of adrenal origin. Although serum 17OHP4 has long been used to monitor treatment of CAH, it correlates poorly with DHEA and AD; furthermore, no good correlation between these routinely measured androgens and clinical evidence of androgen excess has been demonstrated. In addition, routine measurement of AD and T in adults with 21OHD can be confusing, because these steroids also derive from the gonads. A biomarker of androgen production unique to the adrenal gland would be a major advance in the management of 21OHD. We propose as biomarker candidate's 11b-hydroxylated 19- carbon steroids and their 11-keto metabolites, because 11b-hydroxylase (CYP11B1) is expressed only in the adrenal gland and not in the gonad. In addition, other androgens and precursors might be elevated in patients with 21OHD. Recent data has shown elevation of metabolites from the so-called "backdoor pathway" to dihydrotestosterone (DHT) in patients with 21OHD. These intermediates emerge via an enzymatic cascade initiated by the 5�-reduction of 17OHP4, which bypasses the intermediacy of DHEA, AD, or T to the most potent androgen, DHT. In addition, we hypothesize that the abundance of D4-androgens in these patients is facilitated by disrupted adrenal expression of androgenic enzymes and cofactors, conferring the adrenal a gonadal-like zone. The proposed studies aim to (1) determine the zonal distribution of key androgenic enzymes and cofactors within the adrenal cortex in patients with 21OHD and (2) to characterize in detail the adrenal androgen and intermediates in 21OHD, which derive via traditional and novel pathways, with the ultimate goal of identifying adrenal-specific biomarkers of androgen excess. In Aim 1, we will immunostain normal adrenal tissue and adrenal glands obtained from patients with 21OHD and ACTH-dependent Cushing syndrome for CYB5A and 3b-hydroxysteroid dehydrogenase type 2 (HSD3B2), two enzymes necessary for androgen synthesis, but normally expressed in different adrenal zones. We hypothesize that 21OHD and chronic ACTH stimulation disrupt the normal adrenal enzyme distribution, contributing to excessive androgen synthesis. In Aim 2, we will characterize steroid profiles using liquid chromatography-tandem mass spectrometry analysis of blood samples obtained from patients with classic and non-classic 21OHD and from normal controls.

描述（由申请人提供）：21-羟化酶缺乏症（21OHD）是先天性肾上腺增生最常见的形式，也是最常见的遗传性疾病之一。所有21OHD患者的一个显著特征是肾上腺雄激素过量。这些雄激素来源于前体的积累，如17-羟孕酮（17OHP4），靠近有缺陷的酶步骤，在辅助因子蛋白细胞色素b5 （CYB5A）的刺激下，通过包括类固醇17-羟化酶/ 17,20 -裂解酶（CYP17A1）在内的可达途径转化为睾酮(T)。脱氢表雄酮（DHEA），它的硫酸盐（DHEAS）和雄烯二酮（AD）被认为是肾上腺来源的主要雄激素前体。虽然血清17OHP4长期以来一直用于监测CAH的治疗，但它与脱氢表雄酮和AD的相关性很差；此外，这些常规测量的雄激素与雄激素过量的临床证据之间没有良好的相关性。此外，成人21OHD患者的AD和T的常规测量可能会令人困惑，因为这些类固醇也来自性腺。肾上腺独有的雄激素产生生物标志物将是21OHD治疗的重大进展。我们推荐11b羟基化的19-碳类固醇及其11-酮代谢物作为生物标志物，因为11b-羟化酶（CYP11B1）仅在肾上腺中表达，而不在性腺中表达。此外，其他雄激素和前体可能在21OHD患者中升高。最近的数据显示，在21OHD患者中，从所谓的“后门途径”到双氢睾酮（DHT）的代谢物升高。这些中间体通过酶促级联产生，由17OHP4的5°还原引发，绕过脱氢表雄酮、AD或T的中间体，产生最有效的雄激素DHT。此外，我们假设这些患者中d4雄激素的丰富程度是由于雄激素酶和辅助因子的肾上腺表达中断而促进的，从而使肾上腺具有性腺样区。本研究旨在(1)确定21OHD患者肾上腺皮质内关键雄激素酶和辅助因子的区域分布；(2)详细表征21OHD中肾上腺雄激素和中间体，这些激素和中间体通过传统和新型途径产生，最终目标是确定雄激素过量的肾上腺特异性生物标志物。在Aim 1中，我们将对21OHD和acth依赖性库欣综合征患者的正常肾上腺组织和肾上腺进行CYB5A和3b-羟基类固醇脱氢酶2型（HSD3B2）的免疫染色，这两种酶是雄激素合成所必需的，但通常在不同的肾上腺区表达。我们假设21OHD和慢性ACTH刺激破坏了正常的肾上腺酶分布，导致过量的雄激素合成。在Aim 2中，我们将使用液相色谱-串联质谱分析从经典和非经典21OHD患者以及正常对照中获得的血液样本来表征类固醇谱。