膜結合型ペプチダーゼ阻害剤ベスタチンの卵胞発育促進作用の解析

诱导排卵是大多数不孕症妇女的重要治疗方法。然而，世界上广泛使用的促性腺激素治疗作为主要的促排卵方法，在某些情况下并不能使卵泡在卵巢中生长。在这种情况下，到目前为止还没有有效的窃取手段。因此，需要一种局部调节促性腺激素作用的新的促排卵辅助疗法来解决这一问题。虽然许多研究阐明了细胞因子和生长因子等多种多肽在卵泡发生中起着重要的局部调节作用，但利用这些多肽进行促排卵治疗还没有建立起来。我们报道了几种膜结合型多肽酶在人卵泡中的表达，这些多肽酶被认为可以通过调节生物活性多肽的浓度来局部调控卵巢细胞的功能。此外，使用这些肽酶抑制剂的研究表明，它们可以在局部调节促性腺激素的作用。在这项研究中，我们研究了氨肽酶抑制剂贝斯汀在卵泡发生中的作用，以达到临床使用的目的。人或猪的卵泡、颗粒细胞或卵泡膜细胞的培养表明，Bestatin在促性腺激素刺激下影响这些细胞的卵泡发生和类固醇的生成。尽管目前尚未发现这些膜结合型多肽酶在卵巢中的底物，但贝斯汀的作用途径表明，贝斯汀有可能用于治疗经常引起排卵障碍的多囊卵巢。

Ovulation induction is a very important therapy for most infertile women. However, in some cases, gonadotropin therapy, which is widely used as the main therapy for ovulation induction in the world, cannot make the follicles grow in the ovary. In such cases, there are no effective tfierapies so far. Therefore, a new assisted therapy for ovulation induction that locally regulates the effects of gonadotropin is necessary to solve this problem. Although many studies clarified that various peptides such as cytokines and growth factors play important roles as local regulators in folliculogenesis, a new ovulation induction therapy using these peptides has not been established yet. We reported several membrane-bound peptidases are expressed in human follicle and these peptidases are suggested to locally control the ovarian cell functions by regulating the concentration of bioactive peptides. In addition, the study using inhibitors of these peptidases implied that they regulate the effects of gonadotropin locally. In this study, we examined the effects of bestatin, inhibitor of aminopeptidase, in folliculogenesis for the purpose of clinical use. The culture of human or porcine follicles, granulose cells or theca cells showed that bestatin affected folliculogenesis and steroidogenesis of these cells under gonadotropin stimulation. Although the substrates of these membrane-bound peptidase in ovary has not been found, the way of bestatin's effects suggested that bestatin has possibility to be utilized as therapy for polycystic ovary that often causes the ovulation disturbance