Adriaansen Bas P H, Utari Agustini, Olthaar André J, van der Steen Rob C B M, Pijnenburg-Kleizen Karijn J, Berkenbosch Lizanne, Span Paul N, Sweep Fred C G J, Claahsen-van der Grinten Hedi L, van Herwaarden Antonius E
Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
Department of Pediatrics, Division of Pediatric Endocrinology, Amalia Children's Hospital, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
J Clin Endocrinol Metab. 2025 Apr 22;110(5):e1334-e1342. doi: 10.1210/clinem/dgae591.
Some patients with classic congenital adrenal hyperplasia (CAH) survive without glucocorticoid treatment. Increased precursor concentrations in these patients might lead to higher free (biological active) cortisol concentrations by influencing cortisol-protein binding. In 21-hydroxylase deficiency (21OHD), the most common CAH form, accumulated 21-deoxycortisol (21DF) may further increase glucocorticoid activity. Both mechanisms could explain the low occurrence of symptoms in some patients with untreated classic CAH.
Develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for free cortisol and free 21DF to quantify these steroids in patients with untreated classic CAH before and after Synacthen administration, and compare these concentrations to concentrations measured in patients with nonclassic CAH (NCCAH), other forms of adrenal insufficiency (AI), and controls.
An LC-MS/MS method to measure free cortisol and free 21DF was developed and validated. Total and free serum concentrations of both cortisol and 21DF were measured in patients with untreated classic CAH (n = 29), NCCAH (n = 5), AI (n = 3), and controls (n = 11) before and 60 minutes after stimulation with Synacthen.
Unstimulated total cortisol concentrations of patients with untreated classic CAH (median 109 nmol/L) were lower than in patients with untreated NCCAH (249 nmol/L, P = .010) and controls (202 nmol/L, P = .016), but free cortisol concentrations were similar. Basal free 21DF concentrations were high in patients with 21OHD (median 5.32 nmol/L) and undetectable in patients with AI and controls (<0.19 nmol/L). After Synacthen administration, free 21DF concentrations increased in patients with 21OHD, while free cortisol concentrations did not change.
Free cortisol concentrations in patients with classic CAH were similar to those in controls and patients with NCCAH, indicating comparable cortisol availability. Additionally, patients with 21OHD produce high concentrations of 21DF, possibly explaining the low occurrence of symptoms in some patients with classic 21OHD. Free cortisol and 21DF levels should be considered in evaluating adrenal insufficiency in patients with CAH.
一些经典型先天性肾上腺皮质增生症（CAH）患者在未接受糖皮质激素治疗的情况下存活。这些患者中前体浓度的增加可能通过影响皮质醇与蛋白质的结合导致更高的游离（生物活性）皮质醇浓度。在最常见的CAH类型21 - 羟化酶缺乏症（21OHD）中，积累的21 - 脱氧皮质醇（21DF）可能进一步增加糖皮质激素活性。这两种机制都可以解释一些未经治疗的经典型CAH患者症状发生率较低的原因。
开发并验证一种用于测定游离皮质醇和游离21DF的液相色谱串联质谱（LC - MS/MS）方法，以量化未经治疗的经典型CAH患者在注射促肾上腺皮质激素（Synacthen）前后的这些类固醇，并将这些浓度与非经典型CAH（NCCAH）患者、其他形式肾上腺皮质功能减退（AI）患者及对照组患者所测得的浓度进行比较。
开发并验证了一种用于测量游离皮质醇和游离21DF的LC - MS/MS方法。在未经治疗的经典型CAH患者（n = 29）、NCCAH患者（n = 5）、AI患者（n = 3）及对照组（n = 11）中，于注射Synacthen刺激前及刺激后60分钟测量皮质醇和21DF的总血清浓度及游离血清浓度。
未经治疗的经典型CAH患者未受刺激时的总皮质醇浓度（中位数109 nmol/L）低于未经治疗的NCCAH患者（249 nmol/L，P = 0.010）及对照组（202 nmol/L，P = 0.016），但游离皮质醇浓度相似。21OHD患者的基础游离21DF浓度较高（中位数5.32 nmol/L），而AI患者及对照组患者中未检测到（<0.19 nmol/L）。注射Synacthen后，21OHD患者的游离21DF浓度升高，而游离皮质醇浓度未改变。
经典型CAH患者的游离皮质醇浓度与对照组及NCCAH患者相似，表明皮质醇可用性相当。此外，21OHD患者产生高浓度的21DF，这可能解释了一些经典型21OHD患者症状发生率较低的原因。在评估CAH患者的肾上腺皮质功能减退时应考虑游离皮质醇和21DF水平。
