Parborell Fernanda, Irusta Griselda, Vitale Alejandra, Gonzalez Olga, Pecci Adalí, Tesone Marta
Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Facultad de Ciencias Exactas, Universidad de Buenos Aires, Buenos Aires, Argentina.
Biol Reprod. 2005 Mar;72(3):659-66. doi: 10.1095/biolreprod.104.034454. Epub 2004 Nov 24.
Analogs of GnRH, including agonists (GnRH-a) and antagonists (GnRH-ant), have been widely used to inhibit gonadotropin pituitary release. Aside from the effect of GnRH analogs on the pituitary-gonadal axis, studies have shown that GnRH has extrapituitary effects, particularly on rat and human ovaries. In the present study, we evaluated the direct in vivo effects of the GnRH-a, leuprolide acetate (LA), or the GnRH-ant, Antide (Ant), either singly or together, on ovarian follicular development in prepubertal eCG-treated rats. LA significantly decreased ovarian weight, whereas Ant increased ovarian weight compared with controls; however, coinjection of both compounds had no effect. In addition, LA increased the number of preantral follicles (PFs) and atretic follicles, and decreased the number of early antral follicles (EAFs) and preovulatory follicles (POFs). Coinjection of Ant interfered with this LA effect. Ant alone increased the number of POFs compared with that of controls. Analysis of apoptosis has shown that LA increases the percentage of apoptotic cells in PFs, EAFs, and POFs; however, Ant prevented this effect. In addition, Ant alone decreased the percentage of apoptotic cells in EAFs and POFs. Data have shown that Ant per se inhibited BAX translocation from cytosol to mitochondria and retained cytochrome C in the mitochondria, whereas LA induced cytochrome C release. We conclude that Ant inhibits apoptosis in preovulatory follicles through a decrease of BAX translocation to mitochondria, suggesting that GnRH may act as a physiological intraovarian modulator factor that is able to interfere with follicular development through an increase in apoptotic events mediated by an imbalance among the BCL-2 family members.
促性腺激素释放激素（GnRH）类似物，包括激动剂（GnRH-a）和拮抗剂（GnRH-ant），已被广泛用于抑制垂体促性腺激素的释放。除了GnRH类似物对垂体-性腺轴的作用外，研究表明GnRH具有垂体外作用，特别是对大鼠和人类卵巢。在本研究中，我们评估了GnRH-a醋酸亮丙瑞林（LA）或GnRH-ant Antide（Ant）单独或联合使用对经促性腺激素释放激素（eCG）处理的青春期前大鼠卵巢卵泡发育的直接体内作用。与对照组相比，LA显著降低了卵巢重量，而Ant增加了卵巢重量；然而，两种化合物同时注射则没有效果。此外，LA增加了窦前卵泡（PFs）和闭锁卵泡的数量，减少了早期窦状卵泡（EAFs）和排卵前卵泡（POFs）的数量。Ant与LA同时注射会干扰这种作用。单独使用Ant时，与对照组相比，POFs的数量增加。凋亡分析表明，LA增加了PFs、EAFs和POFs中凋亡细胞的百分比；然而，Ant可阻止这种作用。此外，单独使用Ant可降低EAFs和POFs中凋亡细胞的百分比。数据表明，Ant本身可抑制BAX从细胞质向线粒体的转位，并使细胞色素C保留在线粒体中，而LA则诱导细胞色素C释放。我们得出结论，Ant通过减少BAX向线粒体的转位来抑制排卵前卵泡中的凋亡，这表明GnRH可能作为一种生理性的卵巢内调节因子，能够通过增加由BCL-2家族成员失衡介导的凋亡事件来干扰卵泡发育。
