Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia
Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia
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DOI：
10.1016/j.jsbmb.2017.12.016
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发表时间：
2018-04-01
影响因子：
4.1
通讯作者：
Wudy, Stefan A.
中科院分区：
文献类型：
--
作者：
Kamrath, Clemens;Wettstaedt, Lisa;Wudy, Stefan A.
肾上腺雄激素过多是由于21-羟化酶缺乏引起的典型先天性肾上腺增生（CAH）的标志。最近，11-氧合C19类固醇，一类高活性的肾上腺源性雄激素，已被描述在CAH患者中。我们的研究目的是阐明11-氧合雄激素在CAH儿童中的意义。我们回顾性分析了190例CAH儿童的糖皮质激素-，17 α-羟孕酮（17 OHP）-，采用气相色谱-质谱法测定了99例3.0-10.9岁典型CAH儿童氢化可的松和氟氢可的松治疗后的雄激素代谢产物。使用健康儿童的参考，将每日尿类固醇代谢物排泄转化为z评分。分别计算雄激素代谢物Z评分，包括雄烯二酮（A4）、睾酮和5 α-二氢睾酮的主要尿代谢物雄酮（AN）、脱氢表雄酮（DHEA）的尿代谢物和肾上腺源性11-氧合雄激素的主要尿代谢物11 β-羟基雄酮（11 OHAN）。采用多元回归分析来分析11 OHAN合成的前体。11 OHAN，皮质醇，和17 OHP代谢物Z分数升高治疗儿童CAH，而AN和DHEA代谢物Z分数正常化或抑制。多元回归分析显示，11 OHAN排泄与21-脱氧皮质醇的相关性最强（β = 0.379; P = .0006），其次为A4（β = 0.280; P = .0008））和17 OHP（β = 0.243; P = 0.04）代谢物排泄。CAH治疗儿童雄激素过量仅仅是由于11-除了已知的从A4的转化之外，还通过从21-脱氧皮质醇的直接转化而衍生的含氧雄激素。11-与传统雄激素相比，氧合雄激素可能是肾上腺雄激素状态和治疗反应的更好生物标志物。
Adrenal androgen excess is the hallmark of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Recently, 11-oxygenated C19 steroids, a class of highly active adrenal-derived androgens, have been described in patients with CAH.The aim of our study was to elucidate the significance of 11-oxygenated androgens in children with CAH.We retrospectively analysed 190 daily urinary excretion rates of glucocorticoid-, 17 alpha-hydroxyprogesterone (17OHP)-, and androgen metabolites determined by gas chromatography-mass spectrometry of 99 children aged 3.0-10.9 years with classic CAH on hydrocortisone and fludrocortisone treatment. Daily urinary steroid metabolite excretions were transformed into z-scores using references of healthy children. Androgen metabolite z-scores were separately calculated for androsterone (AN), the major urinary metabolite of androstenedione (A4), testosterone and 5 alpha-dihydrotestosterone, for urinary metabolites of dehydroepiandrosterone (DHEA), and for 11 beta-hydroxyandrosterone (11OHAN), the major urinary metabolite of adrenal-derived 11-oxygenated androgens. Multivariate regression analysis was applied to analyse the precursors of 11OHAN synthesis.11OHAN, cortisol-, and 17OHP metabolite z-scores were elevated in treated children with CAH, whereas AN and DHEA metabolite z-scores were normalized or suppressed. Multivariate regression analysis revealed that 11OHAN excretion was strongest associated with 21-deoxycortisol (beta = 0.379; P = .0006), followed by A4 (beta = 0.280; P = .0008)) and 17OHP (beta = 0.243; P = .04) metabolite excretion.Androgen excess in treated children with CAH is solely due to elevated 11-oxygenated androgens that derive in addition to the known conversion from A4 also by direct conversion from 21-deoxycortisol. 11-Oxygenated androgens may represent better biomarkers of adrenal androgen status and treatment response than conventional androgens.