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翻译文献 | 高雄激素状态:评估女性高雄激素状态的一些新视角

2018-10-11 17:13 来源: 中国妇产科网 作者: 中国妇产科网 浏览量: 252

雄激素代谢产物的识别

睾酮在5α还原酶的作用下转化为二氢睾酮,其主要的葡糖醛酸化雄激素代谢产物可以通过质谱分析被测量(74)。它们可以提供进一步值得研究的重大综合问题。有趣的是,研究发现DHEAS是PCOS患者中葡糖醛酸化雄激素强有力的独立预测因子(74)。

随着具有雄激素活性的11-氧合类固醇激素的识别,尤其是最近对11-酮-睾酮和11-酮二氢睾酮的特性描述,人们过去以为的睾酮是最主要天然的雄激素(107)的认知受到了挑战(107)。此外,丰富的11-氧合类固醇的前体物质肾上腺C19类固醇11β-羟基雄烯二酮(11OHA4)和超性能集合色谱-串联质谱(UPC2-MS/MS)法的应用,开辟理解雄激素过多的新视角(108)。O ' reilly 等(109)精美的描述了11-氧合雄激素占了PCOS妇女循环雄激素的绝大部分,肥胖PCOS妇女比非肥胖PCOS妇女具有更高的11OHA4水平,其与代谢紊乱标志物(BMI、空腹胰岛素和Homa指数)关系密切。胰岛素可以直接增加雄激素激活酶1C3型醛酮还原酶 (AKR1C3)的表达以及在PCOS女性中雄激素的促脂肪生成效应的作用,为确立雄性激素过多与女性代谢功能障碍间相互作用的研究开辟了新视野(110)。

对高雄激素状态实验室检测的主要建议

分析标准化对检测结果的正确解释至关重要。通过同种激素检测标准的引入,实验室检测的标准化已经取得了进展。然而,许多自动测定类固醇激素的方法并不能提供令人满意的结果。对于检测结果的解释,需要更多的了解没有卵巢或代谢紊乱妇女群体的激素正常浓度范围和缺陷(111,112)。

激素测定的外部客观质量评定 (EQA)

自20世纪80年代以来,内部检测方法逐渐被商业自动化检测方法所取代,这给制造商带来了一个特殊的责任,即确保可靠的检测设计和校准方法,这些校准方法使得医院实验室可以验证检测方法的分析性能。

显然,医院和卫生保健系统的基础设施和管理因国家政策和认证制度而异。确保正确实施是临床医生、实验室工作人员、诊断系统制造商和医疗监管机构的多学科的责任。因此,所有这些专业团队都对外部质量评估(EQA)感兴趣。EQA是一种审计工具,它可以降低不准确激素评估风险所需的改进方法,这对诊断内分泌系统疾病是至关重要的(112)。自1977年起,包括法国在内的几个国家的里昂生物学家协会(ProBioQual)就开始进行EQA了(13)。参与的实验每年接受6次冻干对照血清,用于检测包括睾酮在内的多种分析物。随着时间推移,对检测结果的分析已总结出了一些结果。绝大多数的实验室(95%以上)检测总睾酮都是常规采用各种免疫分析法,且没有事先进行提取或纯化。对照血清的检测值有相当大的差距,而对照血清的睾酮浓度接近于在妇女中所发现的浓度。这些变化的产生是由于测定试剂盒的差异,以及在这种浓度水平上大多数分析工具缺乏精确度。这种检测结果的分散随对照样本睾酮浓度的增加而减小,在睾酮达到与男性体内相似的浓度时,这种分散是可接受的(13)。睾酮检测的局限性在内分泌学会(28)的一份立场声明中得到了总结,并推动了CDC激素标准化项目(113,114,115)。表2列出了直接睾酮免疫分析法的优缺点。

1.png 

评估过量雄性激来源的决策是建立在单一的总睾酮分析上

当睾酮的水平比正常水平的上限高出2倍(或超出正常均值2个标准差)时,它将提示出一种雄激素分泌型的肿瘤。在这种情况下,必须测量硫酸脱氢表雄酮。硫酸脱氢表雄酮水平> 600µg / dL提示雄激素分泌型肾上腺癌(通常与肾上腺皮质功能亢进相关)。在不同寻常的情况下,地塞米松试验可以抑制功能性肾上腺源肿瘤的雄性激素产生,而促性腺激素释放激素(GnRH)激动剂也可以提供帮助,有助于鉴别卵巢雄性激素分泌型肿瘤和卵巢滤泡膜细胞增生症。

当睾酮的水平仅仅是高于正常上限时,最可能的诊断是多囊卵巢综合征。然而,应进行对于21-羟基化酶缺乏症的非典型病例的筛查(基础17OH-孕酮测定及促肾上腺皮质激素刺激试验),并依赖于临床背景,排除库欣氏病。最后,∆4-雄烯二酮已经与睾酮进行了区分研究,并已经报道了仅有孤立的雄烯二酮升高而没有睾酮升高的患者,特别是在性激素结合球蛋白水平降低的情况下,而其本质上是与代谢综合征相关的。

总结

总睾酮水平的升高是女性高雄激素状态的主要指标。质谱分析法以其较高的准确度提供了测量睾酮水平的最佳工具。考虑到性激素结合球蛋白是主要的睾酮转运蛋白,其水平在很多情况下都很低,包括超重、胰岛素抵抗和中度的炎症状态等,因此对于测定游离睾酮水平的最佳方法还存在争议。然而,最近的一项综述对游离激素假说及其解释提出了挑战,并提出了睾酮与性激素结合球蛋白结合的一种多步骤的动态变构模型,依据性激素结合球蛋白的亲和性是可变的假设和结晶学数据,显示出每一个性激素结合球蛋白均结合了两个睾酮分子而不是一个(116)。这一概念尚未得到独立的验证。

另一种选择是只测量性激素结合球蛋白作为这些疾病的标记,因为其对这些疾病的发生起了部分作用,尤其是在多囊卵巢综合症的病理生理过程中。通过使用质谱分析方法,不仅在血液中,而且在尿液和各种组织中,已经获得雄性激素前体物质和代谢产物的几近完整的轮廓。这将为未来理解和治疗女性雄性激素过量失调一个新的领域。

 

 

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翻译:周瑶

单位:广州市南方医院

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