Rice S, Christoforidis N, Gadd C, Nikolaou D, Seyani L, Donaldson A, Margara R, Hardy K, Franks S
Institute of Reproductive and Developmental Biology, Department of Obstetrics and Gynaecology, Imperial College London, London.
Hum Reprod. 2005 Feb;20(2):373-81. doi: 10.1093/humrep/deh609. Epub 2004 Nov 11.
Insulin resistance and hyperinsulinaemia are well-recognized characteristics of anovulatory women with polycystic ovary syndrome (PCOS) but, paradoxically, steroidogenesis by PCOS granulosa cells remains responsive to insulin. The hypothesis to be tested in this study is that insulin resistance in the ovary is confined to the metabolic effects of insulin (i.e. glucose uptake and metabolism), whereas the steroidogenic action of insulin remains intact.
Granulosa-lutein cells were obtained during IVF cycles from seven women with normal ovaries, six ovulatory women with PCO (ovPCO) and seven anovulatory women with PCO (anovPCO). Mean body mass index was in the normal range in all three groups. Granulosa-lutein cells were cultured with insulin (1, 10, 100 and 1000 ng/ml) and LH (1, 2.5 and 5 ng/ml). Media were sampled at 24 and 48 h and analysed for glucose uptake, lactate production and (48 h only) progesterone production.
Insulin-stimulated glucose uptake by cells from anovPCO was attenuated at higher doses of insulin (100 and 1000 ng/ml) compared with that by cells from either ovPCO (P=0.02) or controls (P=0.02). Insulin and LH stimulated lactate production in a dose-dependent manner, but insulin-dependent lactate production was markedly impaired in granulosa-lutein cells from anovPCO compared with either normal (P=0.002) or ovPCO (P<0.0001). By contrast, there was no difference in insulin-stimulated progesterone production between granulosa-lutein cells from the three ovarian types.
Granulosa-lutein cells from women with anovPCOS are relatively resistant to the effects of insulin-stimulated glucose uptake and utilization compared with those from normal and ovPCO, whilst maintaining normal steroidogenic output in response to physiological doses of insulin. These studies support the probability of a post-receptor, signalling pathway-specific impairment of insulin action in PCOS.
胰岛素抵抗和高胰岛素血症是多囊卵巢综合征（PCOS）无排卵女性的公认特征，但矛盾的是，PCOS颗粒细胞的类固醇生成对胰岛素仍有反应。本研究要验证的假设是，卵巢中的胰岛素抵抗仅限于胰岛素的代谢作用（即葡萄糖摄取和代谢），而胰岛素的类固醇生成作用保持完整。
在体外受精周期中，从7名卵巢正常的女性、6名排卵型PCO女性（ovPCO）和7名无排卵型PCO女性（anovPCO）获取颗粒黄体细胞。三组的平均体重指数均在正常范围内。将颗粒黄体细胞与胰岛素（1、10、100和1000 ng/ml）和促黄体生成素（LH，1、2.5和5 ng/ml）一起培养。在24小时和48小时采集培养基样本，分析葡萄糖摄取、乳酸生成以及（仅48小时）孕酮生成情况。
与ovPCO组细胞（P = 0.02）或对照组细胞（P = 0.）相比，更高剂量胰岛素（100和1000 ng/ml）时，anovPCO组细胞受胰岛素刺激的葡萄糖摄取减弱。胰岛素和LH以剂量依赖性方式刺激乳酸生成，但与正常组（P = 0.002）或ovPCO组（P < 0.0001）相比，anovPCO组颗粒黄体细胞中胰岛素依赖性乳酸生成明显受损。相比之下，三种卵巢类型的颗粒黄体细胞中，胰岛素刺激的孕酮生成没有差异。
与正常和ovPCO女性相比，anovPCOS女性的颗粒黄体细胞对胰岛素刺激的葡萄糖摄取和利用作用相对抵抗，而对生理剂量胰岛素的类固醇生成输出保持正常。这些研究支持PCOS中胰岛素作用存在受体后、信号通路特异性损伤的可能性。
