LH调节女性雄激素生成的分子信号通路研究进展

LH-inducing Pathways in Androgen Biosynthesis of Ovarian Theca-cells

卵巢雄激素合成于卵泡膜细胞,并依赖于黄体生成激素(LH)的刺激作用,由LH下游众多信号通路精密调控,包括传统的环磷酸腺苷-蛋白激酶A-环磷酸腺苷反应元件结合蛋白(c AMP-PKA-CREB)、PKA-细胞外调节蛋白激酶(ERK)、Ras-Raf-MEK-ERK、磷脂酰肌醇3激酶(PI3K)-Akt等信号通路。卵泡发育过程中,磷脂酶Cβ-磷酸肌醇(PLCβ-IP)通路经非腺苷酸环化酶依赖途径激活,介导LH峰作用下颗粒细胞的最终分化。近年研究发现,Wnt、m TORC1等经典信号通路也与卵巢雄激素调节有关,并与其他经典信号通路之间存在复杂的网状交互作用,共同调控卵泡膜细胞雄激素生成。转录调节因子SET作为多任务蛋白,在多种组织中广泛表达,在卵泡膜细胞中通过抑制下游PP2A增加雄激素生成酶P450c17裂解酶活性,促进雄激素合成。LH调控通路过度激活与多种内分泌疾病(如多囊卵巢综合征)有关,并参与妊娠期糖尿病、胰岛素抵抗等多种病理过程。阐明卵泡膜细胞雄激素调控通路对解释雄激素相关疾病尤为重要,是寻找相应疾病治疗方法的基础。就LH作用于卵巢卵泡膜细胞调节雄激素生成的主要通路进行综述。

LH is postulated to regulate exactly the androgen biosynthesis in ovarian theca-cells. LH plays its roles by numerous downstream pathways, including conventional pathways like c AMP-PKA-CREB, PKA-ERK,Ras-Raf-MEK-ERK and PI3K-Akt. LH can stimulate adenylate cyclase（AC）-independed phospholipase C-inositol phosphate（PLC-IP） signaling in ovulatory-size follicles, by which LH induces the differentiation response of granulosa cells. Those classical pathways like Wnt and m TORC1 are related to the androgen biosynthesis in ovaries. The conventional pathways and above classical pathways such as Wnt signaling could act in concert to regulate the ovarian steroidogenesis though the complicated crosstalk. SET protein as a transcriptional regulating factor is widely expressed in various tissues and mediates diverse biological processes. It was recently found that a specific, SET-initiated and PP2A-mediated pathway would lead to the increased lyase activity of P450c17 and the increased testosterone production in ovarian theca cells, which maybe contribute to clarify the hyperandrogenism of polycystic ovarian syndrome（PCOS）. It is important to clarify the pathways involved in the androgen biosynthesis in ovarian theca cells and the hyperandrogenism of PCOS for the treatment of those androgen-related diseases. This review focused on the LH-inducing pathways in regulating steroidogenesis in ovarian theca-cells.