Larrea F, Vilchis F, Chávez B, Pérez A E, Garza-Flores J, Pérez-Palacios G
Department of Reproductive Biology, Instituto Nacional de la Nutrición S. Zubirán, Mexico City, Mexico.
J Steroid Biochem. 1987;27(4-6):657-63. doi: 10.1016/0022-4731(87)90134-8.
In this communication, a series of studies from our laboratory dealing with the mechanism of action of 17 alpha-ethinyl derivatives of 19-nor testosterone are reviewed. The administration of norethisterone (NET) to long-term castrated female rats induces the nuclear translocation of pituitary estradiol receptors and is followed by some estrogenic-like effects at the hypothalamic-pituitary unit. It is established that an A-ring reduced metabolite of NET, the 3 beta,5 alpha-tetrahydro NET derivative, is responsible for the observed in vivo estrogenic effects of the parent compound. 3 beta,5 alpha-NET binds to the estrogen receptor and is efficient in inducing the pituitary estrogen-dependent progesterone receptor and in increasing the uterine weight in long-term castrated rats. Furthermore, administration of 3 beta,5 alpha-NET and the 5 alpha-reduced metabolite of NET (5 alpha-NET) are able to inhibit the release of gonadotropins in the castrated animal to a greater extent than NET. Moreover, pretreatment with tamoxifen, an estrogen binding site competitor, results in a significant diminution of the antigonadotropic potency of 3 beta,5 alpha-NET but not of the 5 alpha-NET, which is only inhibited by the administration of cyproterone acetate. These findings underline the importance of the metabolic rate of NET for the expression of its biological effects at the hypothalamic-pituitary unit.
在本通讯中，我们回顾了实验室一系列关于19-去甲睾酮17α-乙炔基衍生物作用机制的研究。给长期去势的雌性大鼠服用炔诺酮（NET）会诱导垂体雌二醇受体的核转位，随后在下丘脑-垂体单位出现一些类似雌激素的作用。已证实NET的A环还原代谢产物，即3β,5α-四氢NET衍生物，是母体化合物在体内观察到的雌激素作用的原因。3β,5α-NET与雌激素受体结合，能有效诱导垂体雌激素依赖性孕酮受体，并增加长期去势大鼠的子宫重量。此外，给予3β,5α-NET和NET的5α-还原代谢产物（5α-NET）比NET更能抑制去势动物中促性腺激素的释放。此外，用雌激素结合位点竞争剂他莫昔芬预处理会导致3β,5α-NET的抗促性腺激素效力显著降低，但5α-NET不受影响，5α-NET仅通过给予醋酸环丙孕酮来抑制。这些发现强调了NET代谢率对其在下丘脑-垂体单位表达生物学效应的重要性。
