臺灣非肥胖之多囊性卵巢症候群患者性荷爾蒙 及脂肪酸代謝與其相關基因多型性之探討

The Study of Polymorphisms in Genes of Sex Hormones and Lipid Metabolism in Non-obese Women of Polycystic Ovary Syndrome in Taiwan

吳昭嫻(Chao-Hsien Wu)

指導教授 ： 黃士懿

臺北醫學大學/公共衛生暨營養學院/保健營養學研究所/碩士(2011年)

https://doi.org/10.6831/TMU.2011.00082

摘要

多囊性卵巢症候群(polycystic ovary syndrome, PCOS)為育齡婦女普遍的生殖內分泌疾病之ㄧ，約影響5~10%的育齡婦女。其臨床特徵有高雄性激素徵狀(hyperandrogenism)、排卵失調(disordered ovulation)、無月經(amenorrhea)、多毛症(hirsutism)、不孕(infertility)、血脂異常及肥胖等。本研究為探討五個與性荷爾蒙及脂質代謝相關之基因多型性對於台灣非肥胖PCOS患者(身體質量指數<24)的影響，並觀察該基因與生化數值之間的關聯性，並探討台灣非肥胖PCOS患者其血漿中游離脂肪酸的特殊性。本研究於臺北醫學大學附屬醫院分別招募40位BMI及年齡相符合之PCOS患者及月經正常的健康婦女。根據2003年鹿特丹會議(ESHRE/ASRM)所訂定之診斷標準進行收案。招募後進行體位測量、生化數值之檢測，及檢驗CYP17、CYP19、SHBG、PPAR-γ及PLA2五種基因之多型性，並分析其血漿、游離脂肪酸及紅血球細胞膜脂肪酸組成。非肥胖之PCOS患者血清之LH、LH/FSH ratio、TT、FAI、DHEAS、androstenedione皆顯著高於健康女性 (all p<0.05)，而SHBG則顯著較低(p=0.03)。非肥胖PCOS患者之CYP17基因多型性與健康婦女比較呈現顯著差異(p=0.01)；且發現對偶基因C發生變異頻率顯著高於T (p=0.02)；當基因型為CC時，會增加6.11倍罹患PCOS的風險。CYP17的基因變異與TT、FAI、LH有顯著正相關(p=0.01, p=0.01, p=0.009)，但與CYP19 enzyme activity (aromatase)有顯著負相關(p=0.04)。然而CYP19、SHBG、PPAR-γ及PLA2基因多型性與其相對應之產物濃度並無關聯。非肥胖之PCOS患者紅血球細胞膜上的多元不飽和脂肪酸(PUFA)顯著低於健康婦女，而血漿中PUFA顯著高於健康婦女。另外，游離脂肪酸之飽和及不飽和脂肪酸組成百分比於兩組間亦無顯著差異。由本研究結果發現CYP17 (rs743572)的基因變異會增加罹患PCOS的風險並與高雄性激素臨床表徵具顯著相關性。

關鍵字

非肥胖 ； 多囊性卵巢症候群 ； 高雄性激素癥狀 ； 單一核苷酸多型性 ； CYP17 (P450c17)

並列摘要

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy, affecting approximately 5–10% of reproductive-age women. Clinical symptoms involve hyperandrogenism, disordered ovulation, amenorrhea, hirsutism, infertility, dislipidemia and obesity. The aim of this study was to elucidate five polymorphism of sex hormones and lipid-linked metabolism genes of non-obese (body mass index, BMI<24) women with PCOS in Taiwan, and observed the relationship (relevance) between genes and selected biochemical data. We recruited 40 BMI- and age-matched Taiwanese women with PCOS and healthy women with normal menstruation in each group, respectively in Taipei Medical University－Wan Fang medical center. The diagnosis of PCOS was based on the Rotterdam conference criteria in 2003. Anthropometric measurements and selected biochemical markers were analyzed. Five single nucleotide polymorphisms (SNPs) of sex hormones, insulin and lipid-linked metabolism genes (CYP17, CYP19, SHBG, PPAR-γ and PLA2) were detected. The fatty acids profile of plasma, free fatty acid and red blood cell membrane were analyzed in all subjects. In results, we found serum luteinizing hormone (LH), LH/follicle stimulating hormone (FSH) ratio, total testosterone (TT), free androgen index (FAI), dehydroepiandrosterone sulfate (DHEAS), androstenedione, cholesterol and low density lipoprotein-cholesterol (LDL-C) levels in non-obese women with PCOS were significant higher than healthy women (all p<0.05). The sex hormone binding globulin (SHBG) level was significant lower in non-obese women with PCOS than in healthy women (p=0.03). According to our data, we found the genotype of SNPs of CYP17 in women with PCOS was significant different from healthy women (p=0.011)；furthermore the mutation of the C allele frequency was significantly higher than T (p=0.017). In PCOS subjects, while the CC genotype of PCOS subjects that increase 6.11 times the risk of suffering from PCOS. There were positive correlation between gene mutation of CYP17 and TT、FAI、LH (r=0.28, p=0.01; r=0.28, p=0.01; r=0.29, p=0.009, respectively) and negative correlation with CYP19 enzyme activity (p=0.041). However, CYP19, SHBG, PPAR-γ and PLA2 polymorphism and their corresponding biochemical levels were not related. In fatty acid profile, there were significant higher level of PUFA in plasma and lower level of PUFA in red blood cell (RBC) of patients with PCOS, respectively. However, there was no difference of saturated and unsaturated fatty acids of free fatty acids between two groups. In conclusion, the study suggests that genetic variation of CYP17 (rs743572), T convert to C, may increase the risk of non-obese PCOS in Taiwan, which presents significantly relevant to hyperandrogenism.

並列關鍵字

non-obese ； polycystic ovary syndrome ； hyperandrogenism ； single nucleotide polymorphisms (SNPs) ； CYP17 (P450c17)

參考文獻

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