Mifsud A, Ramirez S, Yong E L
Department of Obstetrics and Gynaecology, National University of Singapore, Republic of Singapore.
J Clin Endocrinol Metab. 2000 Sep;85(9):3484-8. doi: 10.1210/jcem.85.9.6832.
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.
高雄激素血症目前被认为是多囊卵巢综合征（PCOS）发病机制的核心，PCOS是一种绝经前女性常见的内分泌紊乱疾病，其特征为月经不规律和无排卵性不孕。尽管高雄激素血症是其特征之一，但一些PCOS女性的血清雄激素水平正常。所有雄激素均通过X连锁雄激素受体（AR）发挥作用，该受体的N端结构域包含一个由高度多态性的CAG三核苷酸重复序列编码的聚谷氨酰胺序列。最近，该CAG微卫星序列的变异虽然仍在正常多态性范围内（11 - 38个CAG），但已与受体活性呈负相关。因此，短序列与高内在AR活性以及雄激素调节的肿瘤前列腺癌的严重程度增加和发病年龄提前相关，而较长的CAG序列与低AR活性和少精子症不育相关。为了研究CAG重复序列在PCOS中的作用，我们测量了91例经超声诊断为多囊卵巢、月经周期不规律和无排卵性不孕患者的CAG重复序列长度，并将其与112例月经规律且已证实有生育能力的对照受试者进行比较。从白细胞DNA中扩增出包含CAG重复序列的荧光标记DNA片段，并在自动DNA测序仪上与内部大小标记物比较其长度。当同时考虑两个等位基因或分别考虑时，患者和对照之间的平均CAG长度没有差异。由于有一部分PCOS患者的血清雄激素水平正常，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高于该值的患者之间CAG长度的差异。与T大于1.73 nmol/L的无排卵患者相比，T小于1.73 nmol/L的无排卵患者的平均CAG双等位基因长度有降低的趋势（22.47±0.36 vs. 23.25±0.29）。当仅考虑每个个体的较短等位基因时，低T水平和高T水平患者之间的CAG长度差异（20.38±0.51 vs. 21.98±0.29）非常显著（P = 0.004）。我们的数据中种族差异也很明显；印度受试者的AR - CAG长度明显短于中国受试者，分别为22.08±0.50和23.16±0.17。我们的数据表明CAG重复序列短长度与血清雄激素水平低的无排卵患者亚组之间存在关联，提示这些患者多囊卵巢的致病机制可能是由于与短AR等位基因相关的内在雄激素活性增加。
