Increased Activation of the Alternative "Backdoor" Pathway in Patients with 21-Hydroxylase Deficiency: Evidence from Urinary Steroid Hormone Analysis
Increased Activation of the Alternative "Backdoor" Pathway in Patients with 21-Hydroxylase Deficiency: Evidence from Urinary Steroid Hormone Analysis
复制标题
DOI：
10.1210/jc.2011-1997
复制
发表时间：
2012-03-01
影响因子：
5.8
通讯作者：
Wudy, Stefan A.
中科院分区：
文献类型：
--
作者：
Kamrath, Clemens;Hochberg, Ze'ev;Wudy, Stefan A.
背景：17-羟孕酮(17-OHP)可通过另一条绕过传统中间体雄烯二酮和睾酮的“后门”途径转化为双氢睾酮(DHT)。在这个后门途径中，17-OHP被转化为5α-孕烷-3α，17α-二醇-20-酮(Pdiol)，这是CYP17A1 17，20裂解酶活性产生雄酮的良好底物。目的和假设：本研究的目的是获得21-羟基酶缺乏症(21-OHD)患者存在后门途径的证据。方法：我们比较了142例未经治疗的21-OHD患者(年龄1d~25.4岁；51名男性)和138名对照组的尿类固醇激素谱。后门途径的活性是用尿中戊二醇浓度与经典的Delta(4)和Delta(5)途径的代谢物的比值来评估的。与几乎完全来自经典途径的黄胆酮不同，雄酮可能另外来自后门途径。结果：未经治疗的21-OHD患者尿中Pdiol/Delta(4)和Delta(5)途径代谢物的比例增加，雄酮与Delta5途径代谢物的比率较高。结论：21-OHD患者的Pdiol/Delta(4)和Delta(5)途径代谢物的比率升高以及雄激素/致病胆汁酮的比率较高表明出生后后门途径的活动在婴儿期最活跃。我们的数据为21-OHD的雄激素生物合成的病理生理学提供了新的见解。(J临床内分泌Metab 97：E367-E375,2012)
Background: 17-Hydroxyprogesterone (17-OHP) can be converted to dihydrotestosterone (DHT) via an alternative "backdoor" route that bypasses the conventional intermediates androstenedione and testosterone. In this backdoor pathway, 17-OHP is converted to 5 alpha-pregnane-3 alpha,17 alpha-diol-20-one (pdiol), which is an excellent substrate for the 17,20 lyase activity of CYP17A1 to produce androsterone.Objective and Hypotheses: The objective of this study was to obtain evidence for the presence of the backdoor pathway in patients with 21-hydroxylase deficiency (21-OHD).Methods: We compared urinary steroid hormone profiles determined by gas chromatography-mass spectrometry of 142 untreated 21-OHD patients (age range, 1 d to25.4 yr; 51 males) with 138 control subjects. The activity of the backdoor pathway was assessed using the ratios of the urinary concentrations of pdiol to those of the metabolites of the classic Delta(4) and Delta(5) pathways. In contrast to etiocholanolone, which originates almost exclusively from the classic pathways, androsterone may be derived additionally from the backdoor pathway. Therefore, the androsterone to etiocholanolone ratio can be used as an indicator for the presence of the backdoor pathway.Results: Untreated 21-OHD subjects showed increased urinary ratios of pdiol to the Delta(4) and Delta(5) pathway metabolites and a higher androsterone to etiocholanolone ratio.Conclusions: The elevated ratios of pdiol to the Delta(4) and Delta(5) pathway metabolites as well as the higher androsterone to etiocholanolone ratio in patients with 21-OHD indicate postnatal activity of the backdoor pathway with maximum activity during early infancy. Our data provide new insights into the pathophysiology of androgen biosynthesis of 21-OHD. (J Clin Endocrinol Metab 97: E367-E375, 2012)