Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty.
Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty.
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DOI：
10.1210/jc.2015-4101
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发表时间：
2016-06
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影响因子：
--
通讯作者：
Arlt W
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文献类型：
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作者：
Idkowiak J;Taylor AE;Subtil S;O'Neil DM;Vijzelaar R;Dias RP;Amin R;Barrett TG;Shackleton CH;Kirk JM;Moss C;Arlt W
类固醇硫酸酯酶 (STS) 可裂解类固醇硫酸盐的硫酸部分，包括硫酸脱氢表雄酮 (DHEA) 硫酸酯 (DHEAS)，即肾上腺雄激素前体 DHEA 的无活性硫酸酯。 DHEA 硫酸化不足（与 STS 催化的酶促反应相反）会通过增加 DHEA 向活性雄激素的转化而导致雄激素过量。由于 X 连锁 STS 基因缺失或失活突变导致的 STS 缺陷（STSD）表现为鱼鳞病，但 STSD 中的雄激素合成和代谢尚未得到详细研究。我们对 30 名患有 STSD 的男性（年龄 6-27 岁；13 名青春期前、5 名青春期前后和 12 名青春期后）和 38 名年龄、性别和 Tanner 阶段匹配的健康对照进行了一项横断面研究。通过质谱法进行血清和 24 小时尿液类固醇代谢组分析，并通过多重连接依赖性探针扩增和桑格测序对 STS 基因进行遗传分析。遗传分析显示所有患者均存在STS突变，其中27个基因完全缺失，1个基因内缺失和2个错义突变。 STSD 患者的青春期发育明显正常。 STSD 患者血清和 24 小时尿 DHEAS 升高，而血清 DHEA 和睾酮降低。然而，24 小时尿雄激素排泄总量与对照组相似，有证据表明 STSD 患者 5α-还原酶活性增加。青春期前健康对照者的血清 DHEA 与 DHEAS 比率显着增加，而青春期后对照者和任何青春期阶段的 STSD 患者均不存在这种情况。在 STSD 患者中，5α-还原酶活性的增加似乎可以通过增强受影响患者的外周雄激素激活来补偿雄激素生成率的降低。在健康对照中，我们发现青春期前血清 DHEA 与 DHEAS 的比率出现了 STSD 中不存在的激增，表明青春期前 STS 活性在生理上上调。这可能代表了组织特异性雄激素激活的微调机制，为青春期雄激素产生的重大变化做好准备。 “类固醇代谢组分析显示，类固醇硫酸酯酶 (STS) 缺乏症中存在轻度雄激素缺乏和 5α 还原酶活性代偿性增加，以及青春期前健康男孩的 STS 活性上调。”
Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet. We carried out a cross-sectional study in 30 males with STSD (age 6–27 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing. Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage. In STSD patients, an increased 5α-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty. “Steroid metabolome analysis reveals mild androgen deficiency and compensatorily increased 5alpha-reductase activity in steroid sulfatase (STS) deficiency and upregulation of STS activity in healthy boys before puberty.”