二甲双胍抑制人颗粒细胞中卵泡刺激素（FSH）的作用：与多囊卵巢综合征的相关性。
Metformin inhibits follicle-stimulating hormone (FSH) action in human granulosa cells: relevance to polycystic ovary syndrome.
机构信息
Division of Biomedical Sciences, St. George's University of London, Cranmer Terrace, Tooting, London SW17 0RE, United Kingdom.
出版信息
J Clin Endocrinol Metab. 2013 Sep;98(9):E1491-500. doi: 10.1210/jc.2013-1865. Epub 2013 Jul 11.
BACKGROUND
Women with anovulatory polycystic ovary syndrome (PCOS) are generally insulin-resistant and as a consequence are often treated with the biguanide metformin. Results with metformin have, however, been variable with some studies demonstrating induction of regular cycles and an increase in ovulation, whereas others do not. Hence more understanding is needed regarding the mechanism of metformin's actions in ovarian granulosa cells especially in light of previous demonstrations of direct actions.
OBJECTIVE
The aim of this study was to investigate metformin's interaction with the FSH/cAMP/protein kinase A pathway, which is the primary signaling pathway controlling CYP19A1 (aromatase) expression in the ovary.
METHODS
The effect of metformin on FSH and forskolin-stimulated aromatase expression in human granulosa cells was measured by quantitative real-time PCR. Activity was assessed after transfection with a promoter II-luciferase construct, and by an RIA measuring conversion of androgen to estrogens. The effect on FSH receptor (FSHR) mRNA was assessed by quantitative PCR. Levels of phosphorylated cAMP response element binding protein (CREB) and CREB-regulated transcription coactivator 2 (CRTC2) were measured by Western blotting and cAMP by a bioluminescent assay.
RESULTS
Metformin markedly reduced FSH but not forskolin-stimulated aromatase expression and activity. This effect was exerted by inhibition of basal and ligand-induced up-regulation of FSHR expression. Metformin also reduced FSH-induced phosphorylation of CREB and hence CRE activity, which could potentially disrupt the CREB-CREB-binding protein-CRTC2 coactivator complex that binds to CRE in promoter II of the aromatase gene. This is mediated in an AMP-activated protein kinase-independent manner, and does not involve alteration of cAMP levels.
CONCLUSION
These finding have implications for the use of metformin in the treatment of anovulation in women with PCOS.
背景
患有排卵障碍型多囊卵巢综合征（PCOS）的女性通常存在胰岛素抵抗，因此常接受二甲双胍类药物二甲双胍治疗。然而，二甲双胍的疗效存在差异，一些研究表明其可诱导正常排卵周期，而另一些研究则不支持。因此，我们需要更多地了解二甲双胍在卵巢颗粒细胞中的作用机制，特别是鉴于之前已经证明其具有直接作用。
目的
本研究旨在探讨二甲双胍与促卵泡激素（FSH）/环磷酸腺苷（cAMP）/蛋白激酶 A（PKA）通路的相互作用，该通路是控制卵巢中 CYP19A1（芳香酶）表达的主要信号通路。
方法
通过定量实时 PCR 测量二甲双胍对人颗粒细胞中 FSH 和 forskolin 刺激的芳香酶表达的影响。通过启动子 II-荧光素酶构建体转染评估活性，并通过 RIA 测量雄激素向雌激素的转化来评估活性。通过定量 PCR 评估 FSH 受体（FSHR）mRNA 的影响。通过 Western 印迹测量磷酸化 cAMP 反应元件结合蛋白（CREB）和 CREB 调节转录共激活因子 2（CRTC2）的水平，并通过生物发光测定法测量 cAMP 的水平。
结果
二甲双胍显著降低了 FSH 但不降低 forskolin 刺激的芳香酶表达和活性。这种作用是通过抑制基础和配体诱导的 FSHR 表达上调来实现的。二甲双胍还降低了 FSH 诱导的 CREB 磷酸化，从而降低了 CRE 活性，这可能破坏结合在芳香酶基因启动子 II 上的 CREB-CRE 结合蛋白-CRTC2 共激活因子复合物。这种作用是 AMP 激活蛋白激酶非依赖性的，并且不涉及 cAMP 水平的改变。
结论
这些发现对 PCOS 女性排卵障碍的二甲双胍治疗具有重要意义。
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