Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Department of Pediatrics, Nijmegen, Netherlands.
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine, Nijmegen, Netherlands.
J Clin Endocrinol Metab. 2019 Nov 1;104(11):5065-5072. doi: 10.1210/jc.2019-00547.
We describe the clinical features and biochemical characteristics of a unique population of severely affected untreated patients with congenital adrenal hyperplasia (CAH) from an Indonesian population with proven cortisol deficiency but without clinical signs of cortisol deficiency. We evaluated the in vitro glucocorticoid activity of all relevant adrenal steroid precursors occurring in patients with CAH.
Cross-sectional cohort study and translational research.
INTERVENTION/MAIN OUTCOME MEASURES: Adrenal steroid precursor concentrations before and 60 minutes after ACTH administration to 24 untreated patients with CAH (3 to 46 years) with proven cortisol deficiency (<500 nmol/L post-ACTH) measured by liquid chromatography-tandem mass spectrometry were compared with six control patients (Mann-Whitney U test). Glucocorticoid receptor (GR) activation was determined by dual-luciferase assays in human embryonic kidney cells transfected with the GR and exposed to increasing amounts of adrenal steroid precursors for 24 hours.
Blood concentrations of the steroid precursors 11-deoxycortisol (457 nmol/L, P = 0.003), 11-deoxycorticosterone (55 nmol/L, P = 0.003), 17-hydroxyprogesterone (610 nmol/L, P < 0.001), progesterone (29 nmol/L, P < 0.001), and 21-deoxycortisol (73 nmol/L) were strongly elevated compared with control subjects. The GR was activated with comparable potency to cortisol by corticosterone and 21-deoxycortisol or with 4 to 100 times lower potency by 11-hydroxyprogesterone, 11-deoxycortisol, aldosterone, 11-deoxycorticosterone, progesterone, and 17-hydroxyprogesterone.
We identified strongly elevated adrenal steroid precursor concentrations in blood from untreated patients with CAH and demonstrated glucocorticoid activity of these adrenal precursors in vitro, suggesting a possible role of these precursors in the clinical phenotype of these patients. Further studies are necessary to evaluate the role of these precursors in more detail.
我们描述了来自印度尼西亚人群中一组未经治疗的先天性肾上腺皮质增生症（CAH）患者的临床特征和生化特征，这些患者存在证实的皮质醇缺乏但无皮质醇缺乏的临床体征。我们评估了所有相关肾上腺类固醇前体在 CAH 患者中的体外糖皮质激素活性。
横断面队列研究和转化研究。
干预/主要观察指标：通过液相色谱-串联质谱法测量 24 例未经治疗的 CAH 患者（3 至 46 岁）在 ACTH 给药前后（60 分钟）证实皮质醇缺乏（ACTH 后<500 nmol/L）的肾上腺类固醇前体浓度，与 6 例对照患者进行比较（Mann-Whitney U 检验）。通过双荧光素酶测定法，在转染了糖皮质激素受体（GR）的人胚肾细胞中测定 GR 的激活，并用不同浓度的肾上腺类固醇前体孵育 24 小时。
11-脱氧皮质醇（457 nmol/L，P = 0.003）、11-脱氧皮质酮（55 nmol/L，P = 0.003）、17-羟孕酮（610 nmol/L，P <0.001）、孕酮（29 nmol/L，P <0.001）和 21-脱氧皮质醇（73 nmol/L）的前体类固醇浓度与对照组相比明显升高。皮质酮和 21-脱氧皮质醇以与皮质醇相当的效力激活 GR，而 11-羟孕酮、11-脱氧皮质醇、醛固酮、11-脱氧皮质酮、孕酮和 17-羟孕酮的效力则低 4 至 100 倍。
我们在未经治疗的 CAH 患者的血液中发现了明显升高的肾上腺类固醇前体浓度，并在体外证明了这些肾上腺前体的糖皮质激素活性，这表明这些前体可能在这些患者的临床表型中发挥作用。需要进一步研究来更详细地评估这些前体的作用。
