背景:Adrenarche是儿童中期的正常发育事件,其特征是肾上腺雄激素分泌增加。经典雄激素途径的作用已经在肾上腺素中得到了很好的描述,但是新的活性雄激素和其他雄激素途径的作用尚不清楚。
目的:研究新型雄激素和相关的类固醇生物合成途径对肾上腺素发生的贡献,并确定肾上腺的其他类固醇生物标志物。
方法:对基线时6-8岁儿童的纵向研究,随访年龄为8-10岁和14-16岁。共包括34名儿童(20名女孩),这些儿童在8-10岁时有临床和/或生化体征(病例)和24名儿童(11名女孩)没有这些体征(对照)。通过液相色谱高分辨率质谱法进行血清类固醇分析。
方法:孕激素中的32种类固醇,糖皮质激素和盐皮质激素途径,和四种雄激素相关途径,包括经典,后门,11-oxy,和11-oxy后门路径。
结果:经典和11-氧雄激素途径更活跃,和经典的主要雄激素的血清浓度(脱氢表雄酮,硫酸脱氢表雄酮,雄烯二酮和雄酮)和11-氧基(11β-羟基雄烯二酮,11β-羟基睾酮,11-酮雄烯二酮,在6-8岁和8-10岁的病例中,11-酮雌酮)途径较高。肾上腺年龄(8-10岁)的孕烯醇酮浓度和青春期(14-16岁)的皮质醇浓度较高。11β-羟基雄酮和11-酮雄酮在有临床症状的病例中倾向于高于仅有肾上腺素生化证据的病例,尽管它们被检测到的水平很低。在生物标志物分析中,计算类固醇与皮质醇的比例,可的松,或11-脱氧可的松作为除分剂比单一类固醇是更好的肾上腺皮质激素分类器。在这些比率中,雄烯二酮/可的松是最好的。
结论:经典和11-氧雄激素途径在肾上腺中具有活性。肾上腺素发生时间较早的儿童在青春期后期血清皮质醇水平较高,提示早期肾上腺素可能通过增加糖皮质激素途径的活性而对肾上腺类固醇生成产生长期影响。未来的研究应采用全面的类固醇谱分析来定义肾上腺和过早肾上腺的新分类器和生物标志物。
BACKGROUND: Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in
adrenarche, but the role of newer active androgens and additional androgen pathways is less clear.
OBJECTIVE: To study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of
adrenarche.
METHODS: A longitudinal study of children aged 6-8 years at baseline, followed up at ages 8-10 and 14-16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8-10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry.
METHODS: Thirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways.
RESULTS: The classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6-8 and 8-10 years. Pregnenolone concentrations at adrenarchal age (8-10 years) and cortisol concentrations at adolescence (14-16 years) were higher in cases. 11β-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best.
CONCLUSIONS: The classic and 11-oxy androgen pathways are active in
adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature
adrenarche.