Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries
Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries
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DOI：
10.1210/jc.85.9.3484
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发表时间：
2000-09-01
影响因子：
5.8
通讯作者：
Yong, EL
中科院分区：
文献类型：
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作者：
Mifsud, A;Ramirez, S;Yong, EL
目前认为高雄激素血症是多囊卵巢综合征(PCOS)发病机制的核心，PCOS是绝经前妇女常见的内分泌紊乱，以月经不调和无排卵性不孕为特征。尽管高雄激素血症是PCOS的特征，但一些患有PCOS的女性血清雄激素水平正常。所有的雄激素都通过X-连锁的雄激素受体(AR)发挥作用，AR的N-末端结构域包含一个由高度多态的CAG三核苷酸重复序列编码的多谷氨酰胺序列。最近，这种CAG微卫星束的变异，虽然保持在正常的多态范围内(11-38个CAG)，但与受体活性呈负相关。因此，短束与内源性AR活性高、雄激素调节肿瘤前列腺癌的严重性和发病年龄较早有关，而CAG束较长与AR活性低和少精子症不育有关。为了探讨CAG重复通道在PCOS中的作用，我们测量了91例超声诊断为多囊卵巢、月经周期不规律和无排卵性不孕症的患者的CAG重复通道长度，并与112例月经正常的正常生育受试者进行了比较。从白细胞DNA中扩增出含有CAG重复序列的荧光标记DNA片段，并在自动DNA测序仪上将它们的长度与内部大小标记进行比较。当两个等位基因一起或单独考虑时，患者和对照组之间的平均CAG长度没有差异。因为有一部分PCOS患者的血清雄激素水平正常，所以我们比较了血清睾酮(T)水平低于正常实验室平均值的患者与血清睾酮水平较高的患者之间CAG长度的差异。T<1.73nmol/L的无排卵患者CAG双等位基因平均长度明显低于T>1.73nmol/L的患者(22.47+/-0.36 vs.23.25+/-0.29)。当只考虑每个个体较短的等位基因时，低T水平患者和高T水平患者之间CAg长度的差异(20.38+/-0.51vs.21.98+/-0.29)非常显著(P=0.004)。在我们的数据中，种族差异也很明显；印度受试者的AR-CAG长度显著短于中国受试者，分别为22.08+/-0.50和23.16+/-0.17。我们的数据表明短CAG重复长度与低血清雄激素的无排卵患者亚群有关，提示这些患者多囊卵巢的发病机制可能是由于短AR等位基因导致的内源性雄激素活性增加所致。
Hyperandrogenism is currently thought to be central to the pathogenesis of polycystic ovarian syndrome (PCOS), a common endocrine disorder in premenopausal women characterized by irregular menstruation and anovulatory infertility. Although hyperandrogenism is characteristic, some women with PCOS have normal serum androgen levels. All androgens act through the X-linked androgen receptor (AR), the N-terminal domain of which contains a polyglutamine tract encoded by a highly polymorphic CAG trinucleotide repeat tract. Recently, variations in this CAG microsatellite tract, while remaining within the normal polymorphic range (11-38 CAGs), have been inversely correlated with receptor activity. Thus, short tracts are associated with high intrinsic AR activity and increased severity and earlier age of onset of the androgen-regulated tumor prostate cancer, whereas longer CAG tracts are associated with low AR activity and oligospermic infertility. To investigate the role of the CAG repeat tract in PCOS, we measured its length in 91 patients with ultrasound diagnosis of polycystic ovaries, irregular menstrual cycles, and anovulatory infertility and compared them to 112 control subjects of proven fertility with regular menses. Fluorescent-labeled DNA fragments containing the CAG repeat tract were amplified from leucocytic DNA, and their lengths were compared with internal size markers on an automated DNA Sequencer. There were no differences in the mean CAG length between patients and controls when both alleles were considered together or separately. Because there is a subset of PCOS patients whose serum androgens are normal, we compared differences in CAG length between patients whose serum testosterone (T) levels were below the normal laboratory mean, to those that were higher. There was a trend for a lower mean CAG biallelic length among anovulatory patients with T less than 1.73 nmol/L compared with those whose T was more than 1.73 nmol/L (22.47 +/- 0.36 vs. 23.25 +/- 0.29). This difference in CAG length between patients with low and high T levels (20.38 +/- 0.51 vs. 21.98 +/- 0.29) was highly significant (P = 0.004) when only the shorter allele of each individual was considered. Ethnic differences were also evident in our data; Indian subjects had a significantly shorter AR-CAG length compared with Chinese, being 22.08 +/- 0.50 and 23.16 +/- 0.17, respectively. Our data indicate an association between short CAG repeat length and the subset of anovulatory patients with low serum androgens, suggesting that the pathogenic mechanism of polycystic ovaries in these patients could be due to the increased intrinsic androgenic activity associated with short AR alleles.