Steroidogenic factor-1 as a therapeutic target for of severe ovarian failure

在芳香酶P450的催化下，雄激素的芳构化是雌激素生物合成的关键，也是卵泡发生的异源。在这里，我们研究了颗粒细胞中芳香酶的转录调控，发现类固醇生成因子-1和LRH-1都是与芳香酶近端启动子PII的核半部位结合的重要调控因子。两种转录因子在正常生长卵泡颗粒细胞和黄体细胞中均有表达。从人颗粒细胞建立的COV432细胞株仅表达LRH-1，生长卵泡中的颗粒细胞比SF-L表达更多的LRH-1。颗粒黄体细胞大量表达LRH-1，而卵泡膜黄体细胞几乎只表达SF-1。SF-1或LRH-1的共表达可刺激含有不同长度PII序列的启动子载体的表达。我们还探讨了IL-1b和GnRH激动剂诱导子宫内膜异位症来源的间质细胞芳香化酶的机制。IL-1b通过COX2依赖和COX2非依赖机制增加芳香酶的表达。GnRH激动剂通过激活PKC一过性地刺激芳香酶的表达。在FSH存在的情况下，IGF-1和BMP也能刺激芳香酶的表达。

Aromatization of androgens, catalyzed by aromatase P450, is essential for estrogen biosynthesis, hetero for folliculogenesis. Here we investigated the transcriptional regulation of aromatase in granulosa cells and identify both steroidogenic factor-1 and LRH-1 as important regulatory factors binding to the nuclear half site of proximal promoter PII of aromatase. Both transcriptional factors were expressed in granulosa cell of healthy growing follicles and luteal cells. COV432, a cell lines established from a human granulosa cell, express exclusively LRH-1 and granulosa cells in growing follicle expressed much LRH-1 than SF-l. Granulosa luteal cells expressed much LRH-1, while theca luteal cells almost exclusively expressed SF-1. Co-expression of SF-1 or LRH-1 stimulated the expression of promoter vectors containing various lengths of PII sequences. We also investigated mechanism of IL-lb- and GnRH agonsit- induced induction of aromatase in endometriosis-derived stromal cells. IL-lb increased aromatase expression through COX2-dependent and COX2-independent mechanisms. GnRH agonists transiently stimulated aromatase expression through the activation of PKC. IGF-1 and BMP also stimulated aromatase expression in the presence of FSH.