A NOVEL THERAPEUTIC MODALITY FOR CONGENITAL ADRENAL HYPERPLASIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 前言：儿童先天性肾上腺增生症(CAH&)的标准口服糖皮质激素和盐皮质激素治疗是非生理性的。使用我们的标准护理，患者每天都面临着治疗过度和治疗不足的问题。过度使用类固醇会阻碍生长，并可能导致丘疹症状。治疗不足会导致持续性的高雄激素血症，这会加速生长、骨龄推进和生长中心的早期融合，导致最终成年身高显著受损。高雄激素血症还会导致肾上腺早熟、性早熟、不孕、粉刺和多毛症。目前治疗的所有这些副作用都降低了这些患者的生活质量。因此，CAH仍处于次优管理状态，寻求改善治疗方法显然是合理的。 背景：理想的治疗方法应该是提供最小的糖皮质激素替代剂量，以有效抑制异常的类固醇旁路。LWPES/ESPE合并声明建议给予氢化可的松10-15 mg/m2/天，作为维持治疗。最近的研究报道，青春期前健康男性每天的皮质醇总产量为6.1+/-0.4 mg/m2/天，青春期男性为5.3+/-0.5 mg/m2/天。然而，在临床实践中，抑制雄激素的产生经常需要氢化可的松15-25毫克/平方米/天，与健康儿童测量的皮质醇产生率(-7毫克/平方米/天)相比，这是过高的(3，4)。 除了正确的剂量，皮质醇治疗成功的其他关键因素是剂量的时机和给药途径。华莱士等人。证实正常儿童ACTH和皮质醇分泌的昼夜节律正常，24小时皮质醇水平也显示持续的基础皮质醇分泌。口服给药(每天服用两到三次皮质醇片剂)代表着间歇性的皮质醇释放，不能模仿健康的肾上腺的持续皮质醇产生。此外，白天服药的时间与ACTH和皮质醇产生自然爆发的时间有很大不同。缺乏一种给予皮质醇的生理手段会产生巨大的临床后果，包括对绝大多数患者的整体激素控制不佳和生活质量下降。 目的：开发一种更生理学的方法，使用可编程胰岛素输注泵治疗儿童和青少年CAH。目的：评价口服氢化可的松对儿童血清皮质醇、17-羟孕酮和血浆ACTH浓度的影响，并探讨皮下注射皮下皮下注射皮下注射皮质醇后这些指标的变化。 我们要检验的假设是： 皮下注射氢化可的松，模拟皮质醇分泌的生理模式，剂量为7 mg/m2/24小时，连续7天，将抑制早起。ACTH激增，导致上午8点正常耗盐性先天性肾上腺增生症(CAH)儿童的血清17-羟孕酮浓度与他们通常口服氢化可的松标准方案的比较。 具体目标 该协议的目的是帮助开发一种更具生理学的方法，使用可编程的胰岛素输注泵来管理患有CAH的儿童和青少年。该方案的长期目标是提供更好的激素控制，防止当前次优治疗方法造成的慢性和不可逆转的后果，并改善食盐消耗性CAH儿童的生活质量。 CAH患儿在常规口服治疗期间和持续皮下皮下注射皮质醇治疗期间，我们将检测血清皮质醇、17-羟孕酮、4-雄烯二酮、睾酮和ACTH的激素浓度，以及24小时尿中17-羟基皮质类固醇和17-酮类固醇的排泄量，并在持续皮下皮下注射皮质醇治疗一周后重复这些测量。 我们将比较两种不同治疗方案的结果，并确定持续皮下注射皮质醇是否抑制上午8点。ACTH激增，导致血清17-羟孕酮浓度正常。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: The standard oral glucocorticosteroid and mineralocorticosteroid therapy of children with congenital adrenal hyperplasia (CAH&) is non-physiological. Using our standard care, patients face both over-treatment and under-treatment throughout each day and across time. Over-treatment with steroids stunts growth and may cause Cushingold features. Under-treatment results in persistent hyperandrogenemia, which accelerates growth, bone age advancement and early fusion of growth centers leading to significantly impaired final adult height. Hyperandrogenemia also causes premature adrenarche, precocious puberty, infertility, acne, and hirutism. All these side effects of the current treatment reduce the qualify of life of these patients. Therefore CAH remained sub-optimally managed and a search for improvement of therapy is clearly justified. Background: The ideal therapy shuld provide the smallest replacement dose of glucocorticoid to effectively suppress the abnormal steroid side pathways. The LWPES/ESPE concensus statement recommendation is to give 10-15 mg/m2/day hydrocortisone, as maintenance therapy. Recent studies have reported total daily cortisol production in healthy pre pubertal males of 6.1+/-0.4 mg/m2/day and in pubertal males 5.3+/-0.5 mg/m2/day (2). However, in the clinical practice suppression of the androgen production frequently requires 15-25 mg/m2/day of hydrocortisone, which is excessive compared to the cortisol production rates measured in healthy children (-7 mg/m2/day) (3,4). Besides the right dose, the other key elements of successful cortisol therapy are, the timing of the dose and the route of administration used. Wallace et al. confirmed normal circadian rhythm of ACTH and cortisol secretion in normal children and the 24-hour cortisol profile displayed continuous basal cortisol secretion, as well (6). The oral administration (taking cortisol tablets two or three times a day) represents intermittent cortisol delivery and cannot mimic the continuous cortisol production of a healthy adrenal gland. In addition, the time when the medication is taken during the day is very much different from the times when the natural bursts of ACTH and cortisol production occur. The lack of a physiologic means of administering cortisol has tremendous clinical consequences including poor overall hormone control and reduced quality of life in the vast majority of patients. Objective: To develop a more physiologic approach to the management of children and adolescents with CAH using a programmable insulin infusion pump. To evluate the serum cortisol, 17-hydroxyprogesterone and plasma ACTH concentrations in children treated with oral hydrocortisone and to investigate these variables in response to subcutaneous basal and bolus cortisol infusions. Our hypothesis to be tested is: subcutaneous infusion of hydrocortisone mimicking physiologic pattern of cortisol secretion at a dose of 7 mg/m2/24 hour for 7 days will suppress the early a.m. ACTH surge and result in mormal 8 a.m. serum 17-hydroxyprogesterone concentration in children with salt wasting Congenital Adrenal Hyperplasia &(CAH) when compared to their standard usual oral hydrocortisone regimen. SPECIFIC AIMS The purpose of this protocol is to help developing a more physiological approach to the management of children and adolescents with CAH using a programmable insulin infusion pump. The long-term objective of the protocol is to provide better hormonal control, to prevent the chronic and solve irreversible consequences of the current sub-optimaltreatment method and to improve the qualify of life of children with salt wasting CAH. In children with CAH we will measure the serum hormone concentrations of cortisol, 17-hydroxy-progesterone, rate of change-4-androstendione, testosterone and ACTH and the 24-hour urinary excretion of 17-hydroxycorticosteroids and 17-ketosteroids -while they are on their usual oral treatment regimen and-during continuous subcutaneous cortisol infusion and will repeat these measurements one week after continuous subcutaneous cortisol infusion treatment. We will compare the results of the two different treatment regimens and determine whether the continuous subcutaneous cortisol infusion suppresses the 8 a.m. ACTH surge and results in normal serum 17-hydroxyprogesterone concentration.