以體內及體外試驗探討高度醣化終產物對性荷爾蒙分泌之影響

Abstract

多囊性卵巢症候群(Polycystic Ovary Syndrome, PCOS)為生育年齡婦女常見的一種內分泌相關疾病，臨床表徵為月經週期紊亂、高雄性素血症及多囊性卵巢的狀況；其致病原因尚無定論，目前研究指出可能與體內荷爾蒙分泌異常及胰島素抵抗有關。顆粒細胞為卵巢中特有的內分泌細胞，可分泌助孕酮及轉換體內雄性素為雌激素，調控月經週期及濾泡發展。醣化終產物(Advanced Glycation End-product, AGEs)能引起發炎、糖尿病併發症等發展，臨床統計上顯示PCOS患者血清中含有較高醣化終產物含量，亦有研究證實攝取高醣化終產物的飲食會影響PCOS患者體內荷爾蒙及提升氧化壓力。本研究以卵巢顆粒細胞株(KGN)及初代卵巢顆粒細胞為平台，以甲基乙二醛(Methylglyoxal, MG)、甘油醛(Glyceraldehyde, GA)、乙二醛(Glyoxal, GO)、乙醇醛(Glycolaldehyde, GOA)及葡萄醣(Glucose, GLU)與牛血清白蛋白(Bovine serum albumin, BSA)合成之五種不同醣化終產物，從影響細胞生長及生殖內分泌的調節等方面探討醣化終產物於卵巢顆粒細胞的影響，並進一步以體內模式印證。結果顯示五種AGEs皆顯著抑制顆粒細胞株KGN及初代顆粒細胞生長，其中以GOA-BSA效果最為顯著。內分泌調節部分，MG-BSA、GA-BSA及GO-BSA於不同刺激物給予下皆能顯著抑制助孕酮分泌。在動物模式中，給予MG-BSA能顯著促使動物表現胰島素阻抗的狀況及提升肝臟指標酵素天門冬氨酸轉氨酶的表現，且顯著降低體內助孕酮濃度。綜合上述結果，醣化終產物可影響顆粒細胞生長、抑制助孕酮分泌及促胰島素阻抗表現上升等PCOS之相關因子。

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is characterized by menstrual cycle disorders, hyperandrogenism and polycystic ovary morphology. No single etiologic factor fully accounts for the spectrum of abnormalities in the polycystic ovary syndrome. Hormonal abonormality and insulin resistance may be associated with the pathogenesis of PCOS in current study. Granulosa cells are specific endocrine cells in ovaries which regulate menstrual cycle and the development of follicles by secreting progesterone and conversion of androgen to estradiol. Advanced glycation end products (AGEs) are known that can spark the development of inflammation and diabetes complications. Research has shown that serum AGEs level was elevated in women with PCOS. Other studies have indicated that consumption of high-AGEs diet can affect hormone expression and enhance oxidative stress. In the present study, we prepared different AGEs by mixing methylglyoxal (MG), glyceraldehyde (GA), glyoxal (GO), glycolaldehyde (GOA) and glucose (GLU) with bovine serum albumin. Human granulosa cell lines (KGN) and human primary granulosa cells are used to investigate the effects of AGEs on hormonal secretion and the proliferation of ovarian cells. Further effect was confirmed by in vivo study. It was observed that five different AGEs treatments significantly inhibit the proliferation of granulosa cells and the dose-dependence was existed. GOA-BSA has the most significant inhibitory effect. The parts of hormonal secretion, MG-BSA, GA-BSA, GO-BSA significantly inhibit progesterone secretion by different stimulators. MG-BSA can significantly increase insulin resistance, serum aspartate transaminase level and inhibit progesterone release in vivo. In conclusion, AGEs can affect granulosa cells proliferation, progesterone secretion and insulin resistance which are risk factors of PCOS.